Intravenous Immunoglobulin Treatment of Immunodeficiency

Foreword

The Question of When and How

Rafeul Alam, MD, PhD Consulting Editor

Replacement immunoglobulin therapy saves lives. When a patient is deficient in immunoglobulins and is unable to produce antibodies in response to pathogens, the rationale for immunoglobulin replacement therapy is straightforward. The rationale becomes more problematic when the immunoglobulin level is only mildly reduced or the antibody response is partial. How do we decide which of these patients will respond to immunoglobulin therapy and which will not? What are the minimum criteria for the initiation of immunoglobulin therapy? These are very important issues that all practitioners struggle with. Once we decide on immunoglobulin therapy, the immediate next questions are: which preparation and what route? The issues at stake are the quality of available immunoglobulins, IgA content, the amount of salt, sugar, blood-derived nonimmunoglobulin products, stabilizing agents, preservatives, and finally the pH and osmolality of the solution. Many of these factors contribute to the side-effect profile of the IVIG preparation. The safety and efficacy of subcutaneous immunoglobulin have now been well established. So the question is: which patient is best suited for this treatment as opposed to IVIG? There is a general consensus on the initial dose of immunoglobulin for replacement therapy. The dose needs to be adjusted based upon the treatment response. The trough level of IgG that renders protection from infections and infection-related complications may vary from patient to patient. Third-party payors have their own guidelines for the trough level of IgG, which may not necessarily be protective against infections. We need a consensus guideline for determining the therapeutically effective IgG trough level. Dr. Roifman, a leader in the field, has put together this excellent issue dedicated to IVIG. A group of outstanding experts presents the state of the art on matters that are of

Supported by NIH grants RO1 AI059719 and AI68088, PPG HL 36577, and N01 HHSN272200700048C. Immunol Allergy Clin N Am 28 (2008) xiiixiv doi:10.1016/j.iac.2008.08.001 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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practical importance to clinicians. The value of this issue to practicing immunologists and other physicians is enormous. Rafeul Alam, MD, PhD Division of Immunology and Allergy National Jewish Health University of Colorado Denver Health Sciences Center 1400 Jackson Street Denver, CO 80206, USA E-mail address: alamr@njc.org

Intravenous Immunoglobulin Treatment of Immunodeficiency

Preface

Chaim M. Roifman, MD, FRCPC Guest Editor

Antibody deficiency is the most common clinically significant immunodeficiency. This inability to produce specific antibodies against microbial agents can be caused by defects of B cells, T cells or both arms of the immune system. In addition, selective or universal antibody deficiency can be associated with innate immune defects as well as with a large number of multi-organ syndromes. Invariably, antibody deficiency ultimately leads to susceptibility to life-threatening infections and autoimmune manifestations. Equally consistent is the efficiacy of IgG replacement therapy in preventing infections. Immunoglobulin (Ig) replacement has saved the lives and dramatically reduced morbidity in numerous patients who have primary immunodeficiency, especially in the last 25 years since the introduction of Ig that is suitable for intravenous administration. These products, which were developed by the blood-product pharmaceutical industry, allowed for administration of higher doses that could build IgG trough levels comparable to normal serum homeostasis. Appropriate trough levels can be achieved by monthly administration of IVIg or weekly injections of subcutaneous Ig. Each route of infusion has its advantages and disadvantages, but both are welcomed by patients who can choose which modality would best accommodate their lifestyle. To date, approximately ten percent of patients in North America have chosen the recently introduced subcutaneous route of Ig administration. This issue provides an important review of all aspects of immunoglobulin therapy, including the definition of patients who need this treatment as well as evolution of products and treatment protocols. We also discuss extensively various routes of Ig infusion and their impact on the healthcare system.

Immunol Allergy Clin N Am 28 (2008) xvxvi doi:10.1016/j.iac.2008.08.002 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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DEDICATION
This issue is dedicated to an exceptional leader, Dr. Fred Rosen, who, through ingenuity and extraordinary dedication, elevated the field of primary immunodeficiency to its current stature for the benefit of patients. Chaim M. Roifman, MD, FRCPC Division of Immunology and Allergy Department of Pediatrics The Hospital for Sick Children 555 University Avenue Toronto, ON M5G 1X8 Canada E-mail address: croifman@sickkids.ca

Hypo gammaglobulinaemia
Patrick F.K.Yong, MRCPa,b, Ronnie Chee, MRCP, FRCPathb, Bodo Grimbacher, MDb,*
KEYWORDS     Hypogammaglobulinaemia  Primary immunodeficiency Primary antibody deficiency  Agammaglobulinaemia Common variable immunodeficiency Class switch recombination defects

Hypogammaglobulinemia generally can be divided into primary/genetic causes or secondary causes due to other factors, such as sequelae of certain infectious diseases, malignancy, various medications, including immunosuppressants and anticonvulsants and systemic diseases that result in hypercatabolism or excessive loss of immunoglobulin (Ig).1 Depending on the symptoms and severity of the hypogammaglobulinemia, various treatment options are available including replacement Ig therapy, antibiotic treatment or just careful follow-up observation. The International Union of Immunological Societies (IUIS) has produced regular reports on the classification of primary immunodeficiency diseases (PIDs), with the most recent update in 2007.25 PIDs that resulted in hypogammaglobulinemia were categorized within several groups, which included those that caused a combined T and B cell defect, those that resulted in predominantly antibody deficiency, and those that incorporated other well-defined immunodeficiency syndromes. Other groups of PIDs did not have significant hypogammaglobulinemia, including diseases of immune dysregulation, congenital disorders of phagocyte numbers or function or both, defects in innate immunity, autoinflammatory disorders, and complement deficiencies. This article discusses primarily PIDs that result in hypogammaglobulinemia generally following the order in the most recent IUIS classification (Table 1),5 with particular focus on the more common ones that typically require Ig replacement therapy. Several of the PIDs classified in this section (ie, X-linked lymphoproliferative syndrome, CD40 ligand deficiency, and CD40 deficiency) are also classified elsewhere in the IUIS scheme and are discussed in greater depth elsewhere in this issue because they result from T-cell dysfunction or immune dysregulation. Predominantly antibody deficiency syndromes as a whole make up the greatest proportion of PID diagnosesup 67% to 77% of all PIDs, as recently published by the European and Australian registries.6,7 Of the individual antibody deficiency
B. Grimbacher is funded by EU grant MEXT-CT-2006-042316. a Department of Clinical Immunology, Kings College Hospital, London SE5 9RS, UK b Department of Immunology and Molecular Pathology, UCL Immunology Consortium, Royal Free Hospital and University College London, Pond Street, London NW3 2QG, UK * Corresponding author. E-mail address: b.grimbacher@medsch.ucl.ac.uk (B. Grimbacher). Immunol Allergy Clin N Am 28 (2008) 691713 doi:10.1016/j.iac.2008.06.003 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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Table 1 The International Union of Immunological Societies classification of predominantly antibody deficiencies Disease BTK deficiency m Heavy chain deficiency l5 Deficiency Iga deficiency Igb deficiency BLNK deficiency Thymoma with immunodeficiency Myelodysplasia Genetic Defects BTK/BTK IGHM/m heavy chain CD179B/l5 CD79A/Iga CD79B/Igb BLNK/BLNK Unknown Monosomy 7, trisomy 8, and dyskeratosis congenita have been reported TNFRSF13B/TACI TNFRSF13C/BAFFR MSH5/Msh5 ICOS/ICOS CD19/CD19 SH2D1A/SAP XIAP/XIAP

Severe reduction in all serum Ig isotypes with profoundly decreased or absent B cells

Severe reduction in serum IgG and IgA with normal, low, or very low numbers of B cells Common variable immunodeficiency disorders ICOS deficiency CD19 deficiency X-linked lymphoproliferative syndrome

Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells CD40L deficiency CD40 deficiency Activation-induced cytidine deaminase deficiency Uracil-DNA glycosylase deficiency Ig heavy chain deletions k Chain deficiency Isolated IgG subclass deficiency IgA deficiency associated with IgG subclass deficiency Selective IgA deficiency Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells Transient hypogammaglobulinemia of infancy with normal numbers of B cells TNFSF5/CD154 TNFRSF5/CD40 AICDA/AID UNG/UNG Deletion at chromosome 14q32 Mutation in k constant gene Unknown Unknown Unknown Unknown Unknown

Isotype or light chain deficiencies with normal numbers of B cells

disorders, common variable immunodeficiency (CVID) made up the largest proportion of entries at 31.6% and 38.4% of all PIDs, respectively.
DISEASES RESULTING IN SEVERE REDUCTION IN ALL SERUM IMMUNOGLOBULIN ISOTYPES WITH PROFOUNDLY DECREASED OR ABSENT B CELLS BTK Deficiency/X-linked Agammaglobulinemia

X-linked agammaglobulinemia (XLA), or Brutons agammaglobulinemia, first described in 1952,8 is the prototypic B-cell immunodeficiency resulting in agammaglobulinemia

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because of a block in B-cell maturation. Almost 40 years later, in 1993, two groups identified BTK, the gene responsible for XLA, which encodes a protein tyrosine kinaseBruton tyrosine kinase (Btk).9,10 The disease is typically characterized by marked reduction in serum Ig levels (IgG < 2 g/L, IgA and IgM < 0.2 g/L) and circulating B cells of less than 2%.1 A recent US registry estimated the birth rate for XLA at 1 in 379,000 live births, although this number was thought to be an underestimate.11 Other registry data have estimated a live birth rate as high as 1 in 100,000 in Norway and as low as 1 in 20 million in Spain, however.12,13 Btk is encoded over 19 exons spanning 37 kb at Xq2214 and belongs to the Tec family of cytoplasmic tyrosine kinases.15 It is present in all stages of B-cell differentiation except plasma cells and myeloid cells and platelets but not T cells.16,17 Crosslinking of the B-cell receptor results in phosphorylation and activation of Btk.18 Initially Btk is phosphorylated by src family members and then undergoes autophosphorylation.19 Receptor-associated src family members also phosphorylate the immunoreceptor tyrosine activation motifs on the cytoplasmic tails of Iga and Igb, which escort the m-heavy chain to the cell surface. Full phosphorylation of the immunoreceptor tyrosine activation motifs allows Syk, another cytoplasmic tyrosine kinase to dock and be activated via transphosphorylation.20 Syk then phosphorylates downstream targets, including B-cell linker protein (BLNK).21 This process allows Btk and PLCg2 to bind to BLNK, resulting in phosphorylation of PLCg2 by Btk.22 PLCg2 then generates inositol triphosphate (IP3), a second messenger that binds to receptors on the endoplasmic reticulum leading to calcium release.
Btk mutations

There is significant variability in Btk mutations, with more than 170 different mutations identified and no single mutation accounting for more than 3% of patients in one series.23 The issue as to whether specific mutations are associated with more significant disease has been difficult to clarify, because in addition to the nature of the mutation and compensating genetic factors, the age of first diagnosis is influenced by environmental exposure to infectious organisms, the level of suspicion of the physician, and the amount of antibiotic use. One study does raise the suggestion that patients with less severe mutations (ie, persons with amino acid substitutions or base pair substitutions at sites within the splice consensus site that are conserved, but not invariant) are more likely to have a later diagnosis, higher B-cell percentage, and plasma IgM.24 It should be noted, however, that patients with severe mutations (eg, premature stop codons or mutations in the start codon) can have mild disease 2527 and that patients with the same mutation in the same family can have varying degrees of severity,25,27,28 which implies that other factors play a role in determining outcomes in XLA.
Clinical features

XLA is an X-linked recessive disorder that is fully penetrant and manifests in affected men. In general, female carriers are asymptomatic, although there are rare exceptions to the rule, with a recent case report of a daughter of a man with XLA who had all the features of XLA caused by extremely skewed X-inactivation.29 There is marked variability in the clinical course of patients with XLA. In general, most patients become clinically symptomatic by the age of 1 year with nearly all patients manifesting by the age of 5.11,30 It should be noted that 10% to 25% of patients develop symptoms before 3 to 4 months of age, when some degree of maternal antibody would still be expected to be present.11,30 Most patients had reduced levels of all Ig isotypes and markedly reduced circulating B cells, although in most of the series of

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patients, a handful developed symptoms only after the age of 5 and some had Ig levels within the normal range, despite confirmed Btk mutations.11,31,32 The mean age at diagnosis was 3.5 years in the Italian series31 and 4 years in the Iraninan series.30 The most recent American series showed that patients with a family history were diagnosed at a mean of 2.59 years but patients without a family history were diagnosed significantly later at a mean age of 5.37 years.11 In general, there was an inverse correlation between the age at diagnosis and the year of birth, hopefully indicating greater awareness of the disease.11,30,31 Approximately 25% to 40% of patients had a positive family history at the time of birth;11,31,32 however, even in the most recently published series, only approximately a third of patients with a positive family history were diagnosed before the onset of clinical symptoms.11 This finding indicates the need for improved genetic counseling in affected families. Infection is the commonest feature in XLA before diagnosis and during follow-up. The commonest infections involve the respiratory tract (including pneumonia, sinusitis, and otitis media) and affect 60% to 80% of patients, most commonly with Streptococcus pneumoniae but also with Haemophilus influenzae, staphylococcus, and pseudomonas species.11,3032 Diarrhea affects approximately 25% of patients (most commonly with giardia lamblia but also rotavirus, campylobacter, enterovirus, salmonella, and shigella species).11,3032 A few cases of vaccine-associated paralytic polio and wild polio have been reported in the various case series.11,31,32 A handful of cases of Pneumocystis jirovecii infection was reported despite the fact that Btk mutations are not known to affect T-cell function.11,33,34 This was attributed to poor nutrition in the children affected. One case series described a constellation of symptoms in patients who presented in infancy, including pyoderma gangrenosa, perirectal abscess, cellulitis, or impetigo associated with pseudomonas or staphylococcal sepsis and neutropenia.32 In addition to recurrent infections, patients with XLA also have poorly developed lymphoid tissue, which can be noted clinically in the absence of tonsils and lymph nodes and should alert the clinician to consider the diagnosis. Patients are prone to long-term complications of chronic lung damage and chronic sinusitis from infection; data have shown that the factors that significantly influenced the likelihood of chronic lung damage were higher mean age at diagnosis and duration of follow-up.31 In addition to conventional pathogens, patients with XLA have been noted to be susceptible to certain more unusual infections. Enteroviral infection (eg, coxsackie and echoviruses) can cause meningitis/encephalitis and, more rarely, hepatitis, pneumonia, and dermatomyositis, resulting in significant morbidity and mortality.3538 Mycoplasma arthritis and urethritis were reported in 7 of 52 patients with XLA in one study,39 although the more recent case series did not note this as a frequent complication.11,30,31 The incidence of malignancy in XLA is unclear. Gastric adenocarcinoma, lung cancer, lymphoproliferative disease, dermatofibrosarcoma protuberans, and colorectal cancer have been reported to occur in patients who have XLA.11,4044 There was an increase in colorectal cancer in 3 of 52 patients in one report43 but no other cases in two series of 4445 and 73 patients,31 respectively, and only one case in the largest series of 201 patients.11 Without formal epidemiologic studies, it is not possible to state definitively if patients with XLA are more prone to malignancy and if any tumors occur more frequently.
Autosomal Recessive Agammaglobulinemia

Approximately 15% of patients with congenital agammaglobulinemia and absent circulating B cells do not have a mutation in Btk.23 Mutations in the m heavy chain

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(IGHM) are thought to account for approximately 20% to 30% of patients without Btk mutations.46,47 Defects in l5 (CD179B), Iga (CD79A), Igb (CD79B), and BLNK (BLNK) have been identified in a small number of patients with autosomal recessive agammaglobulinemia.4853 In approximately 5% to 10% of all patients with defects in early B-cell development, no clear molecular defect has been identified. Clinically, patients with the autosomal recessive forms of agammaglobulinemia are not easily distinguishable from patients with XLA, although there is heterogeneity in the clinical presentation. Patients with m heavy chain deficiency, for example, were noted to generally present at an earlier age with a higher incidence of complications, although two patients in one series had a relatively mild course and were still alive at age 53 and 49 years despite receiving what would currently be considered suboptimal doses of Ig.46
Thymoma with Immunodeficiency

The association of thymoma with immunodeficiency or Goods syndrome was originally described in 1955,54 and although there is no formal diagnostic criteria, it is recognized as a separate entity in the IUIS classification.5 Patients generally present in their 50s,55 but Goods syndrome can occur in children.56 It occurs with a similar frequency in men and women. Immunodeficiency can either precede or follow the diagnosis of the thymoma and does not resolve with thymectomy.55 The etiology of Goods syndrome is not clear, although three possible hypotheses have been suggested: (1) the possibility that cytokines (eg, limitin in a murine model) can cause B-cell arrest or impair maturation, (2) the loss of the naive or memory T-cell population (and thereby the T-cell help for B cells) in view of the opportunistic infections, and (3) autoimmune destruction of the B cells in view of the studies in thymoma patients showing that T cells or autoantibodies can inhibit erythropoiesis.57 Clinically, these patients are susceptible to recurrent infection with encapsulated bacteria and diarrhea,55 similar to other patients with agammaglobulinemia. Susceptibility to opportunistic infections also suggests a cell-mediated defect. Cytomegalovirus colitis and retinitis and chronic mucocutaneous candidiasis occur relatively frequently;55 infections with P jirovecii pneumonia, human herpesvirus 8, herpes simplex, varicella zoster, and babesiosis have been reported.5659 Autoimmune phenomena, including myasthenia gravis, pure red cell aplasia, pernicious anemia, diabetes mellitus, polymyositis, and idiopathic thrombocytopenia, also can occur.2,58 Prognosis is generally thought to be worse compared to other antibody deficiency syndromes. In one series, 10 years after diagnosis only 33% of patients who had Goods syndrome were alive compared to 95% of patients with XLA or CVID.45 The increased mortality was thought to be caused by disease complications (eg, infection, autoimmune disease, and hematologic complications) rather than the underlying thymoma, although patient numbers in the largest series were small (7 patients who had Goods syndrome vs 240 patients who had CVID). Apart from the reduced/absent B cells and hypogammaglobulinemia, various other immunologic abnormalities have been described, including abnormal CD41/CD81 T-cell ratios, CD41 lymphopenia, and reduced T-cell proliferation to mitogens.60
Myelodysplasia

Myelodysplastic syndromes can mimic XLA, and this diagnosis has been included in the most recent IUIS classification.5,61 A small number of pediatric patients have been reported in the literature. They can have monosomy 7, trisomy 8, or dyskeratosis congenita and recurrent infection and low B cells at the onset of disease and the pancytopenia associated with myelodysplasia.6163 These patients can have normal specific

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antibody titers and isohemagglutinins titers and low numbers of pro- and pre-B cells in the bone marrow (unlike patients with XLA who have normal numbers of pro-B cells).62,63
SEVERE REDUCTION IN SERUM IgG AND IgA WITH NORMAL, LOW, OR VERY LOW NUMBERS OF B CELLS Common Variable Immunodeficiency

The first description of CVID in 1953 has been credited to Janeway.64 It is currently understood to be a heterogenous group of predominantly antibody deficiency disorders that make up the greatest proportion of patients with symptomatic primary hypogammaglobulinemia, with an estimated population prevalence of between 1in 10,000 and 1 in 50,000.2 Clinically, it is defined by the presence of recurrent infection, a reduction in IgG (of at least two standard deviations below the mean), and at least one other Ig isotype and a failure to generate a significant specific antibody response after vaccination or natural infection after other known genetic or acquired causes of hypogammaglobulinemia have been excluded.1,2
Clinical features

CVID affects both genders equally, and symptoms can begin at any age, although there are peaks in the first and third decades.65 A significant diagnostic delay of between 4 and 9 years exists in the published case series.6,65,66 In approximately 10% of patients, familial clustering of CVID has been documented, although typically the illness is sporadic.67 IgA deficiency (discussed later) can occur in family members of patients with CVID,68 which is consistent with the observation that some patients with IgA deficiency progress to CVID.69 Recurrent infections (with a similar spectrum to patients with agammaglobulinemia, possibly reflecting antibody deficiency rather than the intrinsic genetic defect) are the most frequent complications in CVID. Recurrent respiratory tract infections occur in up to 98% of patients who have CVID.65 Recurrent sinopulmonary infection can result in chronic sinusitis, hearing loss, and bronchiectasis, which are the principal sources of morbidity and (along with lymphoma) mortality in CVID.65 In one cohort, bronchiectasis was present in a third of patients at baseline, with a further 12.2% developing it during follow-up despite appropriate treatment.66 In general, most patients are not more susceptible to most viral infections and opportunistic infections are rare. Similar to patients with agammaglobulinemia, however, there is also infrequently a predisposition to mycoplasma infection of the joints (11 of 306 patients in one series,39 although these numbers were not replicated in another series of similar size)65 and enteroviral meningoencephalitis (with no more than 30 patients identified in the literature, most of whom were on inadequate doses of replacement Ig).37,70 Gastrointestinal disease also occurs frequently in patients who have CVID, affecting up to 20% to 25% of patients.65 The most common infections are with Giardia lamblia, Campylobacter jejuni, and Salmonella species; other prominent findings include nodular lymphoid hyperplasia, inflammatory bowel disease, and nonspecific malabsorption.65 Severe cytomegalovirus enteritis also has been reported.71 Autoimmune disease complicates CVID in up to 20% to 25% of patients. Autoimmune cytopenias (particularly autoimmune thrombocytopenia and autoimmune hemolytic anemia) are the most commonly reported conditions, but various other conditions, including rheumatoid arthritis, sicca syndrome, pernicious anemia, and systemic lupus erythematosus, have been described.65,66 One series reported that the autoimmune thrombocytopenia preceded the hypogammaglobulinemia in 62% of cases.72

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Nonmalignant lymphoproliferation and granulomatous disease have been described in patients who have CVID. Up to a third of patients with CVID can develop lymphoproliferation, which is reflected as splenomegaly, intestinal lymphoid hyperplasia, or lymphadenopathy.65 Lymphoid interstitial pneumonitis also has been reported.73 Granulomatous inflammation most commonly affects the lung and has been reported in 8% to 22% of patients with CVID.65,74,75 Multisystemic involvement is not infrequent; granulomatous disease has been described in lymph nodes, spleen, liver, parotid glands, meninges, and bone marrow76 and is often associated with a poor prognosis.74 Patients with CVID are also at greater risk of malignancy, particularly non-Hodgkins lymphoma and gastric carcinoma, with rates between 18 and 10 to 16 times greater than that of healthy individuals, respectively.65,66,77 Other malignancies, such as colorectal cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, and Waldenstroms macroglobulinemia, also have been described, but numbers in the various series have been too small to determine if there was a significant increased risk.65,66
Immunopathology and classification schemes

A host of immunologic abnormalities have been described in the innate and adaptive immune systems in patients who have CVID.7891 It is unclear if these changes are pathogenic or merely represent epiphenomena. In the innate immune system, abnormalities have been described in monocytes,78 monocyte-derived dendritic cells,7981 and blood myeloid and plasmacytoid dendritic cells.82 Signaling defects in the TLR9 pathway in plasmacytoid dendritic cells and B cells have been reported.83 There has been a greater focus on the adaptive immune system, and multiple T-cell abnormalities in antigen and mitogen-induced proliferation,65 cytokine production,84 generation of antigen-specific T cells after vaccination,85 cell surface molecule expession (CD40L, attractin),86,88 and T-cell apoptosis87 have been described. More recent work has shown elevation in serum IL-7 (which plays a role in homeostatic proliferation of lymphocytes) in a subset of patients who have CVID who had increased numbers of CD81 T cells with decreased apoptosis and a greater incidence of splenomegaly and autoimmunity.89 Abnormalities in T-cell receptor signaling affecting the cytoplasmic guanine nucleotide exchange factor Vav91 and ZAP-7090 have been demonstrated. Based on the immunologic abnormalities seen in patients who have CVID, various classification schemes, mostly based on B-cell phenotype, have been developed to help stratify patients for research and prognostic reasons. Bryant and colleagues92 originally divided patients who have CVID based on the ability of lymphocytes to produce Ig on stimulation in vitro. This method was labor intensive and not widely adopted; subsequently, two flow cytometric classification systems based on memory B-cell phenotype were published.93,94 These systems had some differences, and to further refine these schemes, the EUROClass scheme was developed after a large trial involving 303 patients.95 EUROClass separated patients who had nearly absent B cells (< 1% of lymphocytes), severely reduced switched memory B cells (< 2% of total B cells), and expansion of transitional (> 9% of total B cells) or increased CD21low B cells (> 10% of total B cells). There was a degree of clinical correlation, albeit relatively imprecise, with splenomegaly and granulomas more frequently seen in patients with reduced switched memory B cells and elevated CD21low B cells and lymphadenopathy more frequently seen in patients with elevated transitional B cells. In addition to the B-cell classification schemes, investigators also classified patients who have CVID using T cells96 and dendritic cells,97 with a degree of clinical correlation.

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Genetics

The past few years have seen the discovery of mutations/polymorphisms in five genes that result/contribute to a CVID phenotype, representing a significant advance in the understanding of what was previously poorly understood at a molecular level. The genes identified so far affect inducible costimulator ([ICOS] gene: ICOS) on T cells,98 transmembrane activator and calcium-modulator and cyclophilin ligand interactor ([TACI] gene: TNFRSF13B),99,100 B-cell activating factor receptor ([BAFF-R] gene: TNFRSF13C),101 CD19102,103 (gene: CD19) on B cells, and MSH5, which is involved in regulating meiotic homologous recombination and contributes to class switch recombination (CSR).104
Inducible Costimulator Deficiency

ICOS is expressed on activated T cells and belongs to the CD28 family of costimulatory surface molecules. It plays a significant role in activating T helper cells and providing B-cell help by superinduction of IL-10 necessary for terminal B-cell differentiation into memory and plasma cells and by binding to ICOS-ligand, which is present on antigen-presenting cells, including naive B cells.105,106 So far, a total of nine individuals from four families have been identified with the same homozygous mutation (resulting in a truncated protein) in ICOS since it was first described in 2003.98,107 All affected patients have the same homozygous haplotype at the D2S2289 locus near the ICOS gene; all four families are believed to originate from a common founder and are either linked by the House of Habsburg or the River Danube.107 Phenotypically, ICOS deficiency results in hypogammaglobulinemia and reduced B-cell numbers, particularly in the IgM memory and switched memory B-cell subsets. This further strengthens the evidence that ICOS plays an important role in late B-cell differentiation, class switching, and memory B-cell development.98 Patients who have ICOS deficiency were able to generate IgM responses during infection, however.
TACI Deficiency

TACI is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and belongs to a group of TNFRSF receptors that also includes B-cell maturation antigen and BAFF-R, which play important roles in B-cell survival, development, and antibody production.108 The ligands for TACI and B-cell maturation antigen are BAFF and a proliferation-inducing ligand. Mutations in TACI that result in CVID were first described in 200599,100 and are thought to be present in 8% to 10% of patients with CVID.109 A complicated pattern of inheritance with homozygous, heterozygous, and compound heterozygous mutations were identified, suggesting that there were autosomal dominant and autosomal recessive patterns of inheritance. Extracellular (C104R, S144X), transmembrane (A181E), and intracellular (S194X, R202H, Ins204) portions of the molecule were all found to possess mutations.99,100 The role of heterozygous mutations in CVID is not completely clear because it was subsequently shown that patients with CVID had unaffected family members with the same TACI mutation.110 In a large study, the C104R and A181E (but not the R202H) mutations were present in greater frequency in patients who had CVID compared to the general population.111,112 This finding suggested that TACI mutations (at least in the heterozygous state) might result in increased disease susceptibility rather than being solely responsible. No clear genotype-phenotype correlation has been shown in patients with TACI mutations, although there is a suggestion that these patients are at increased risk of autoimmunity and lymphoid hyperplasia.99

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B-cell Activating Factor Receptor Deficiency

BAFF-R deficiency has so far been identified in only one patienta 60-year-old man who had a 24 base pair homozygous deletion in exon 2, which codes for the transmembrane portion of the receptor.101 This deficiency resulted in a block at the transitional B-cell stage, leading to low total peripheral B-cell numbers and a percentage increase in transitional B cells, indicative of the BAFFBAFF-R role in peripheral B-cell survival. These findings have only been published in abstract form so far; the full publication is awaited.
CD19 Deficiency

CD19 is a B-cell surface molecule that forms a co-receptor complex with CD21, CD81, and CD225. The co-receptor complex reduces the signaling threshold after antigen binding to the B-cell receptor,106 and the CD21 component can bind antigen-bound C3d, thus linking recognition of complement to CD19 signaling.113 Five patients with a CVID phenotype from three families have been found to have a total of four different mutations in CD19.102,103Three patients (born to unrelated Colombian parents) had a homozygous two base pair deletion that resulted in a frameshift and premature stop codon leading to deletion of a large portion of the intracellular domain. One patient (born to consanguineous Turkish parents) had a single base pair insertion that resulted in a frameshift and premature stop codon in the proximal region of the intracellular domain.102 The final patient (born to unrelated Japanese parents) was a compound heterozygote with a splice acceptor site mutation of intron 5 on the maternal allele, which resulted in skipping of exon 6 and a truncated protein, and a gross deletion on the paternal allele that encompassed the CD19 and at least the neighboring ATP2A1 and NFATC2IP genes.103 All patients presented in childhood with recurrent infections and hypogammaglobulinemia. One patient was found to have mild thrombocytopenia, which raised the possibility of autoimmunity.103 Peripheral B-cell numbers were normal, but CD51 and memory B cells were reduced. Patients had normal germinal center formation but poor antibody responses to vaccination. Other publications on patients with CD19 deficiency are underway, which suggests that the defect may not be that rare.
MSH5 Mutations

MSH5 is a gene encoded in the major histocompatibility class III region that plays role in homologous recombination in meiosis but was found to be involved in CSR in mice.104 Subsequently, several nonsynonymous single nucleotide polymorphisms (SNPs) in MSH5 were found in greater frequency in patients who have IgA deficiency (C580G, L85F/P786S, rs3131378) and CVID (Q292H, rs3131378).104 MSH5 was found to have reduced binding affinity to its heterodimerization partner MSH4 in patients who had the L85F/P786S allele. Patients who have CVID with heterozygous nonsynonymous MSH5 polymorphisms were found to have abnormalities in the Sm-Sa1 joints; although controls with heterozygous MSH5 polymorphisms did not have hypogammaglobulinemia, there were some subtle differences in the S joint phenotype. Consequently, it is more likely that MSH5 is a disease susceptibility gene rather than pathogenic.104
X-linked Lymphoproliferative Syndrome

X-linked lymphoproliferative syndrome was originally described in 1974114 as a rapidly fatal illness after Epstein Barr virus infection in men with a strong genetic linkage. The illness can result in fulminant infectious mononucleosis (60% of patients), lymphoma

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(30%), or dysgammaglobulinemia (30%), and patients can present with any or all of these features.115 It also has been recognized that Epstein Barr virus infection is not necessary to trigger the onset of the disease. The mutation responsible for X-linked lymphoproliferative syndrome was identified in the signaling lymphocyte activation moleculeassociated protein ([SAP] gene: SH2D1A) in 1998.116,117 SAP mutations only accounted for approximately 60% of familial X-linked lymphoproliferative syndrome, however, and defects in the gene encoding the X-linked inhibitor of apoptosis (XIAP) were identified in 2006 in a cohort of some of these patients with no molecular diagnosis.118 X-linked lymphoproliferative syndrome can mimic CVID, although in one series only 1 of 60 patients with CVID had an SH2D1A mutation.119
CLASS SWITCH RECOMBINATION DEFECTS: SEVERE REDUCTION IN SERUM IgG AND IgA WITH NORMAL/ELEVATED IgM AND NORMAL NUMBERS OF B CELLS

Reductions in serum IgG and IgA with a normal or elevated IgM are suggestive of a defect in the machinery required for CSR and result in the so-called hyper-IgM syndrome (HIGM), which is somewhat of a misnomer because the IgM can sometimes be in the normal range. These syndromes can be inherited in an X-linked, autosomal recessive or autosomal dominant manner.120 Limited epidemiologic data are available, but X-linked HIGM is thought to have an estimated frequency of approximately 1 in 500,000 live male births in the United States.121 The first mutation that accounted for these syndromes to be discovered was in CD40 ligand ([CD40L] gene: TNFSF5), which results in the X-linked HIGM syndrome that makes up approximately 30% of patients with CSR defects.122,123 CD40L is present on the surface of T cells and interacts with CD40 on the surface of B cells (required for Ig class switching) and dendritic cells/monocytes (required for T cell responses). Patients are susceptible to recurrent bacterial infections similar to other patients with hypogammaglobulinemia but are also prone to infections with opportunistic organisms, such as P jirovecii, cryptosporidium, toxoplasma, and cytomegalovirus, and neutropenia and autoimmune disease.120,121 A mutation in CD40 (gene: TNFRSF5) resulting in a similar clinical phenotype but inherited in an autosomal recessive manner also was described in a small number of patients.124 Another form of an X-linked HIGM syndrome in association with anhidrotic ectodermal dysplasia was described with mutations in NF-kB essential modulator (NEMO or IKKg), which is required for CD40 induced signaling of the transcription factor NF-kB.125,126 CD40L, CD40, and NEMO deficiency all result in a combined antibody and cellular immune deficit and are discussed elsewhere in this issue. The remaining 70% of patients with class switch defects possess some form of intrinsic B-cell defect that is usually inherited in an autosomal recessive (sometimes autosomal dominant) manner. Mutations in activation-induced cytidine deaminase ([AID] gene: AICDA) and uracilDNA glycosylase ([UNG] gene: UNG) have been described to account for approximately 40% of these patients, although there remains a substantial group with an as-yet uncharacterized molecular defect.
Activation-Induced Cytidine Deaminase Deficiency

AID deficiency is typically inherited in an autosomal recessive fashion and is characterized by defects in CSR and somatic hypermutation (SHM).127 Clinically, these patients are prone to recurrent bacterial infections and diarrhea, similar to other patients with hypogammaglobulinemia, but they also frequently possess marked enlargement of lymphoid organs, in contrast to patients with XLA who have sparse lymphoid tissue. Giant germinal centers (five to ten times the normal size) filled with

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intensely proliferating B cells have been found in lymphoid tissue biopsies. This finding is thought to be caused by continuous antigen stimulation due to lack of SHM secondary to defective AID.128 Lymphoid hyperplasia has been noted to decrease with Ig replacement.129 IgM-mediated autoimmunity (mostly cytopenias) is seen in approximately one fourth of these patients.127,129 In a case series of 29 patients, the median age of onset of clinical symptoms was 2 years (range 0.312.9) with recognition of immunodeficiency at 3.8 years and diagnosis of a HIGM syndrome at 4.9 years.129 IgM levels ranged from 1 to 37 g/L, whereas IgG levels ranged from undetectable to 1.5 g/L and IgA ranged from undetectable to 0.2 g/L.129 AID possesses a cytidine deaminase activity domain, an apolipoprotein-B mRNAediting cytidine deaminase 1 (APOBEC-1)-like domain, and a nuclear localization signal and nuclear export signal in the N and C terminal portions of the protein, respectively. It is thought to be essential for initiation of the DNA cleavage required for CSR and SHM; 35 different recessive mutations have been identified in 73 patients.128131 The mechanism by which AID exerts its function is not completely clear, although studies in patients with AID deficiency have helped to shed some light on this. It is thought to act as a DNA-editing enzyme and a docking protein by forming multimeric complexes.132 Mutations in AID generally result in defective CSR and SHM in keeping with its role as the inducer of DNA breaks required for these processes, although mutations in the C-terminal portion in a small number of patients have been shown to result only in defective CSR but not SHM.133 This information and additional data showing that AID truncated for the last ten amino acids was unable to generate CSR but was able to generate mutations in the Sm region134 was taken to indicate that the C-terminal portion of AID played a role in binding a CSR-specific cofactor that helped target AID to Sm regions. A particular heterozygous mutation (R109X) in the C-terminal portion has been shown to result in an autosomal dominant form of a HIGM defect.128,135 This is thought to arise because of a dominant negative effect of the mutated allele, which implies that a multimeric AID complex is necessary for optimal CSR and SHM.
Uracil-DNA Glycosylase Deficiency

A similar clinical picture to AID deficiency with recurrent infections and lymphadenopathy was described in three patients with a homozygous defect in UNG, which is a member of a family of glycosylases able to deglycosylate uracil residues on DNA.136 UNG deficiency results in defective CSR but with SHM in normal frequency, albeit with a biased pattern, with almost all mutations at G/C residues being transitions as opposed to an equal frequency of transitions and transversions at A/T residues.136,137 This finding has been cited as a strong argument for the DNA-editing activity of AID. AID is thought to deaminate cytosine into uracil. Subsequently, UNG deglycosylates and removes the uracil residues, which creates an abasic site and allows creation of single-stranded DNA breaks. UNG deficiency interferes with this pathway and results in defective CSR and skewed SHM.136,137
Uncharacterized Molecular Defects that Result in Deficiencies in Isotype Class Switching

There are still many cases of CSR defects caused by an intrinsic B-cell abnormality that are not caused by AID or UNG deficiency. A CSR defect titled HIGM4 has been described in a group of 15 patients with clinical features similar to AID deficiency, although slightly milder with some residual IgG production.138 The specific defect has yet to be identified, although it is thought to be

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downstream to AID and probably due to a selective defect in either a CSR-specific factor of the DNA machinery or survival signals delivered to B cells. Another defect thought to be upstream of S region DNA cleavage was described in a group of 16 patients with HIGM and a generally good prognosis, with no autoimmunity or lymphoma.128 It was speculated that this condition could be caused by problems with AID targeting (which is poorly understood) to switch regions.
ISOTYPE OR LIGHT CHAIN DEFICIENCIES WITH NORMAL NUMBERS OF B CELLS

Most of the deficiencies in Ig isotypes or light chains occur in otherwise healthy individuals, and the question of Ig replacement is controversial in persons who are symptomatic. They are covered here briefly for completeness.
Immunoglobulin Heavy Chain Deletions

Deletions and duplications that affect the heavy chain constant regions in chromosome 14q32 have been described in 5% to 10% of the healthy white population who have no history of recurrent infection.2,139 One or more IgG and IgA subclasses and IgE have been shown to be affected.139 Homozygous individuals lack the relevant subclasses, and heterozygotes may show diminished levels. Most patients are well, although a few individuals have presented with recurrent infections, which casts doubt on the relevance of the immunologic abnormalities.
k Chain Deficiency

k chain deficiency has been reported in two families.2,140 B cells seemed to be normal, although all of them possessed the l light chain. Point mutations in the k chain gene were reported in one family.141
Isolated IgG Subclass Deficiency

Isolated deficiencies in one or more IgG subclasses were first described in 1970 in patients with recurrent sinopulmonary infections142 and are defined as a reduction in one or more IgG subclasses more than two standard deviations from the mean. By definition, however, approximately 2.3% of the healthy population will have an IgG subclass deficiency and up to 10% to 15% actually do have an IgG4 level below the limit of detection.143 Many healthy individuals have been identified with significantly decreased IgG subclass levels. Consequently, controversy exists as to whether isolated IgG subclass deficiency does represent a true PID. Some authors have argued that there is no clinical value in IgG subclass measurement.144146
Selective IgA Deficiency

Selective IgA deficiency is defined as complete absence of IgA (usually less than the detection limit of 0.07 g/L in most laboratories) with a normal IgG and IgM in patients older than age of 4 and in whom other causes of hypogammaglobulinemia have been excluded. It is the commonest Ig deficiency and has a prevalence of 1 in 300 to 1 in 700 in whites.2,147149 Most patients with IgA deficiency are asymptomatic, although there is an increased prevalence of infections, autoimmune disease, atopy, and celiac disease.150152 There was a suggestion of increased rates of gastrointestinal malignancy and lymphoma in patients who have IgA deficiency,153 but this was not replicated in a later study.154 The molecular mechanisms underlying IgA deficiency are unclear, although as noted in some patients, there is a family history of IgA deficiency and CVID, and some patients can progress to CVID.6769

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IgA Deficiency Associated with IgG Subclass Deficiency

IgG subclass deficiency has been noted to occur in association with IgA deficiency, and both can present with specific antibody deficiency. The molecular, clinical characteristics and frequency of these combined deficiencies in the healthy and patient populations remain poorly understood and characterized, although small studies suggest that a combination of these defects is more likely to result in clinical disease.155
SPECIFIC ANTIBODY DEFICIENCY WITH NORMAL IMMUNOGLOBULIN CONCENTRATIONS AND NORMAL NUMBERS OF B CELLS

Specific antibody deficiency with normal Ig was first described in 1980156 and is characterized by normal levels of IgG, IgA, and IgM but a failure to make antibody responses to vaccination, typically with polysaccharide antigens. Clinically, these patients are prone to recurrent sinopulmonary infections; bronchiectasis, diarrhea, and autoimmune disease also have been reported.157 There is no universal definition as to what constitutes a failure to respond, however. Normal responses are age dependent and not well characterized. Pure polysaccharide antibody responses are unreliable in children younger than age 2 years.158 The components necessary to define what constitutes an adequate response include (1) the increase in antibody titers above baseline, (2) the final antibody concentration, and (3) the percentage of serotypes in the vaccine to which the patient has responded. The American practice parameter defines an adequate response to individual serotypes as a postimmunization antibody titer of 1.3 mcg/mL or more or at least fourfold over baseline.145,158 Patients between 2 and 5 years of age are expected to respond to at least half the vaccinated serotypes; for patients 5 years or older, the consensus recommendation was that there should be a response to 70% of the serotypes, although it was acknowledged that there was a degree of controversy regarding this. The IUIS classification is a lot less specific than this.2 The increasing use of conjugated pneumococcal vaccines in routine immunization is likely to influence how a diagnosis of specific antibody deficiency is made in the future. A further point about the diagnosis of specific antibody deficiency is whether patients who fail to make responses to polysaccharide antigens but not to protein antigens should be considered a separate group than patients who cannot make responses to polysaccharide and protein antigens.159 Much work still needs to be done with regard to diagnosing and working out the molecular mechanisms underlying specific antibody deficiency. The entity does serve to make the point that in patients with normal Ig levels who have recurrent infections, further detailed evaluation is necessary.
TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY WITH NORMAL NUMBERS OF B CELLS

In 1956, Gitlin and Janeway160 described two infants with temporary hypogammaglobulinemia and coined the description transient hypogammagloublinemia of infancy (THI). This was thought to be caused by prolongation of the nadir in gammaglobulins normally seen in infants in the first few months of life after the decline in maternally transferred Ig. Despite this, until now this group of patients remains poorly characterized with little understanding of the molecular mechanisms underlying the condition. The IUIS classification had noted that THI can take up to 36 months to resolve,2 although it has been noted that the period of hypogammaglobulinemia can extend significantly beyond infancy. Only approximately half the infants had resolution of

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hypogammaglobulinemia by 24 months in one case series, with resolution seen at up to 14 years of age,161 and a definitive diagnosis of THI can be made only retrospectively. Patients with THI were more likely to be male (60%80%) and generally presented with mild infections, including ear/nose/throat infections, respiratory infections, and diarrhea,161165 although isolated case reports have documented more severe infection.166 An increased risk of atopic disease has been noted in patients with THI.164,165 Generally, patients with THI have reductions in IgG and IgA below the lower limit of normal and less frequently in IgM; specific antibody production and cell-mediated immunity is usually intact.161,165 A few individuals have reduced vaccine responses that recover by 3 to 4 years.162 Some recent data indicated that in vitro Ig secretory responses were poorer in patients who had THI and that in vitro IgG and IgA (but not IgM) responses did not normalize at the same time as serum Ig.164 This was interpreted as possibly caused by some deficiency in class switch mechanisms.
SUMMARY

The predominantly antibody deficiency PIDs that result in hypogammaglobulinemia represent an important group of diseases, both clinically and for furthering understanding of the immune system. Combined, they represent the largest group of PID diagnoses that possess a relatively good outcome with Ig replacement therapy. A significant delay in diagnosis still remains, which can result in significant morbidity and long-term complications and emphasizes that the need for greater awareness of these conditions still remains. This heterogenous group of disorders has provided many useful insights into our understanding of the immune system, particularly with regard to B-cell development and antibody responses and is likely to continue doing so.
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86. Farrington M, Grosmaire LS, Nonoyama S, et al. CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. Proc Natl Acad Sci U S A 1994;91(3):1099103. 87. Di RM, Serrano D, Zhou Z, et al. Enhanced T cell apoptosis in common variable immunodeficiency: negative role of the fas/fasligand system and of the Bcl-2 family proteins and possible role of TNF-RS. Clin Exp Immunol 2001;125(1): 11722. 88. Pozzi N, Gaetaniello L, Martire B, et al. Defective surface expression of attractin on T cells in patients with common variable immunodeficiency (CVID). Clin Exp Immunol 2001;123(1):99104. 89. Holm AM, Aukrust P, Damas JK, et al. Abnormal interleukin-7 function in common variable immunodeficiency. Blood 2005;105(7):288790. 90. Boncristiano M, Majolini MB, DElios MM, et al. Defective recruitment and activation of ZAP-70 in common variable immunodeficiency patients with T cell defects. Eur J Immunol 2000;30(9):26328. 91. Paccani SR, Boncristiano M, Patrussi L, et al. Defective vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects. Blood 2005;106(2): 62634. 92. Bryant A, Calver NC, Toubi E, et al. Classification of patients with common variable immunodeficiency by B cell secretion of IgM and IgG in response to anti-IgM and interleukin-2. Clin Immunol Immunopathol 1990;56(2):23948. 93. Warnatz K, Denz A, Drager R, et al. Severe deficiency of switched memory B cells (CD27(1)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood 2002;99(5):154451. 94. Piqueras B, Lavenu-Bombled C, Galicier L, et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol 2003;23(5):385400. 95. Wehr C, Kivioja T, Schmitt C, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 2008;111(1):7785. 96. Giovannetti A, Pierdominici M, Mazzetta F, et al. Unravelling the complexity of T cell abnormalities in common variable immunodeficiency. J Immunol 2007; 178(6):393243. 97. Yong PF, Workman S, Wahid F, et al. Selective deficits in blood dendritic cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia but not specific polysaccharide antibody deficiency. Clin Immunol 2008;127(1): 3442. 98. Grimbacher B, Hutloff A, Schlesier M, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 2003; 4(3):2618. 99. Salzer U, Chapel HM, Webster AD, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 2005;37(8):8208. 100. Castigli E, Wilson SA, Garibyan L, et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 2005;37(8):82934. 101. Warnatz K, Salzer U, Gutenberger S. Finally found: human BAFF-R deficiency causes CVID. XIth Meeting of the European Society for Immunodeficiencies. Versailles (France), October 2124, 2004. 102. van Zelm MC, Reisli I, van der BM, et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 2006;354(18):190112.

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103. Kanegane H, Agematsu K, Futatani T, et al. Novel mutations in a Japanese patient with CD19 deficiency. Genes Immun 2007;8(8):66370. 104. Sekine H, Ferreira RC, Pan-Hammarstrom Q, et al. Role for Msh5 in the regulation of Ig class switch recombination. Proc Natl Acad Sci U S A 2007;104(17): 71938. 105. Carreno BM, Collins M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 2002;20:2953. 106. Carter RH, Fearon DT. CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 1992;256(5053):1057. 107. Salzer U, Maul-Pavicic A, Cunningham-Rundles C, et al. ICOS deficiency in patients with common variable immunodeficiency. Clin Immunol 2004;113(3): 23440. 108. Schneider P. The role of APRIL and BAFF in lymphocyte activation. Curr Opin Immunol 2005;17(3):2829. 109. Bacchelli C, Buckridge S, Thrasher AJ, et al. Translational mini-review series on immunodeficiency: molecular defects in common variable immunodeficiency. Clin Exp Immunol 2007;149(3):4019. 110. Zhang L, Radigan L, Salzer U, et al. Transmembrane activator and calciummodulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes. J Allergy Clin Immunol 2007;120(5):117885. 111. Pan-Hammarstrom Q, Salzer U, Du L, et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet 2007;39(4):42930. 112. Castigli E, Wilson S, Garibyan L, et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet 2007;39(4):4301. 113. Fearon DT, Carroll MC. Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu Rev Immunol 2000;18: 393422. 114. Purtilo DT, Cassel C, Yang JP. Letter: fatal infectious mononucleosis in familial lymphohistiocytosis. N Engl J Med 1974;291(14):736. 115. Seemayer TA, Gross TG, Egeler RM, et al. X-linked lymphoproliferative disease: twenty-five years after the discovery. Pediatr Res 1995;38(4):4718. 116. Coffey AJ, Brooksbank RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 1998;20(2):12935. 117. Sayos J, Wu C, Morra M, et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 1998;395(6701):4629. 118. Rigaud S, Fondaneche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 2006;444(7115):1104. 119. Eastwood D, Gilmour KC, Nistala K, et al. Prevalence of SAP gene defects in male patients diagnosed with common variable immunodeficiency. Clin Exp Immunol 2004;137(3):5848. 120. Notarangelo LD, Duse M, Ugazio AG. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev 1992;3(2):10121. 121. Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 2003; 82(6):37384.

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122. Aruffo A, Farrington M, Hollenbaugh D, et al. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 1993;72(2):291300. 123. DiSanto JP, Bonnefoy JY, Gauchat JF, et al. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature 1993;361(6412):5413. 124. Ferrari S, Giliani S, Insalaco A, et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A 2001;98(22):126149. 125. Doffinger R, Smahi A, Bessia C, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 2001;27(3):27785. 126. Jain A, Ma CA, Liu S, et al. Specific missense mutations in NEMO result in hyperIgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2001;2(3): 2238. 127. Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 2000;102(5):56575. 128. Durandy A, Revy P, Imai K, et al. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev 2005;203:6779. 129. Quartier P, Bustamante J, Sanal O, et al. Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency. Clin Immunol 2004;110(1):229. 130. Minegishi Y, Lavoie A, Cunningham-Rundles C, et al. Mutations in activationinduced cytidine deaminase in patients with hyper IgM syndrome. Clin Immunol 2000;97(3):20310. 131. Zhu Y, Nonoyama S, Morio T, et al. Type two hyper-IgM syndrome caused by mutation in activation-induced cytidine deaminase. J Med Dent Sci 2003; 50(1):416. 132. Durandy A, Peron S, Taubenheim N, et al. Activation-induced cytidine deaminase: structure-function relationship as based on the study of mutants. Hum Mutat 2006;27(12):118591. 133. Ta VT, Nagaoka H, Catalan N, et al. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat Immunol 2003;4(9):8438. 134. Barreto V, Reina-San-Martin B, Ramiro AR, et al. C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion. Mol Cell 2003;12(2):5018. 135. Kasahara Y, Kaneko H, Fukao T, et al. Hyper-IgM syndrome with putative dominant negative mutation in activation-induced cytidine deaminase. J Allergy Clin Immunol 2003;112(4):75560. 136. Imai K, Slupphaug G, Lee WI, et al. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol 2003;4(10):10238. 137. Di NJ, Neuberger MS. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 2002;419(6902):438. 138. Imai K, Catalan N, Plebani A, et al. Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class-switch recombination. J Clin Invest 2003;112(1):13642. 139. Brusco A, Cariota U, Bottaro A, et al. Variability of the immunoglobulin heavy chain constant region locus: a population study. Hum Genet 1995;95(3):31926. 140. Zegers BJ, Maertzdorf WJ, Van LE, et al. Kappa-chain deficiency: an immunoglobulin disorder. N Engl J Med 1976;294(19):102630.

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141. Stavnezer-Nordgren J, Kekish O, Zegers BJ. Molecular defects in a human immunoglobulin kappa chain deficiency. Science 1985;230(4724):45861. 142. Schur PH, Borel H, Gelfand EW, et al. Selective gamma-g globulin deficiencies in patients with recurrent pyogenic infections. N Engl J Med 1970;283(12): 6314. 143. Jefferis R, Kumararatne DS. Selective IgG subclass deficiency: quantification and clinical relevance. Clin Exp Immunol 1990;81(3):35767. 144. Maguire GA, Kumararatne DS, Joyce HJ. Are there any clinical indications for measuring IgG subclasses? Ann Clin Biochem 2002;39(Pt 4):3747. 145. Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol 2005;94(5 Suppl 1):S163. 146. Buckley RH. Immunoglobulin G subclass deficiency: fact or fancy? Curr Allergy Asthma Rep 2002;2(5):35660. 147. Clark JA, Callicoat PA, Brenner NA, et al. Selective IgA deficiency in blood donors. Am J Clin Pathol 1983;80(2):2103. 148. Litzman J, Sevcikova I, Stikarovska D, et al. IgA deficiency in Czech healthy individuals and selected patient groups. Int Arch Allergy Immunol 2000;123(2): 17780. 149. Ulfarsson J, Gudmundsson S, Birgisdottir B, et al. Selective serum IgA deficiency in Icelanders: frequency, family studies and Ig levels. Acta Med Scand 1982;211(6):4817. 150. Edwards E, Razvi S, Cunningham-Rundles C. IgA deficiency: clinical correlates and responses to pneumococcal vaccine. Clin Immunol 2004;111(1):937. 151. Hanson LA, Bjorkander J, Carlsson B, et al. The heterogeneity of IgA deficiency. J Clin Immunol 1988;8(3):15962. 152. Alaswad B, Brosnan P. The association of celiac disease, diabetes mellitus type 1, hypothyroidism, chronic liver disease, and selective IgA deficiency. Clin Pediatr (Phila) 2000;39(4):22931. 153. Cunningham-Rundles C, Pudifin DJ, Armstrong D, et al. Selective IgA deficiency and neoplasia. Vox Sang 1980;38(2):617. 154. Mellemkjaer L, Hammarstrom L, Andersen V, et al. Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study. Clin Exp Immunol 2002;130(3): 495500. 155. Bossuyt X, Moens L, Van HE, et al. Coexistence of (partial) immune defects and risk of recurrent respiratory infections. Clin Chem 2007;53(1):12430. 156. Saxon A, Kobayashi RH, Stevens RH, et al. In vitro analysis of humoral immunity in antibody deficiency with normal immunoglobulins. Clin Immunol Immunopathol 1980;17(2):23544. 157. Cheng YK, Decker PA, OByrne MM, et al. Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome. Ann Allergy Asthma Immunol 2006;97(3):30611. 158. Sorensen RU, Leiva LE, Javier FC III, et al. Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations. J Allergy Clin Immunol 1998;102(2): 21521. 159. Kirkpatrick CH. Specific polysaccharide antibody deficiency. Ann Allergy Asthma Immunol 2006;97(3):271. 160. Gitlin D, Janeway C. Agammaglobulinemia, congenital, acquired and transient forms. Prog Hematol 1956;1:31829.

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161. Whelan MA, Hwan WH, Beausoleil J, et al. Infants presenting with recurrent infections and low immunoglobulins: characteristics and analysis of normalization. J Clin Immunol 2006;26(1):711. 162. Dalal I, Reid B, Nisbet-Brown E, et al. The outcome of patients with hypogammaglobulinemia in infancy and early childhood. J Pediatr 1998;133(1):1446. 163. Walker AM, Kemp AS, Hill DJ, et al. Features of transient hypogammaglobulinaemia in infants screened for immunological abnormalities. Arch Dis Child 1994;70(3):1836. 164. Kidon MI, Handzel ZT, Schwartz R, et al. Symptomatic hypogammaglobulinemia in infancy and childhood - clinical outcome and in vitro immune responses. BMC Fam Pract 2004;5:23. 165. Kilic SS, Tezcan I, Sanal O, et al. Transient hypogammaglobulinemia of infancy: clinical and immunologic features of 40 new cases. Pediatr Int 2000;42(6): 64750. 166. Kosnik EF, Johnson JP, Rennels MB, et al. Streptococcal sepsis presenting as acute abdomen in a child with transient hypogammaglobulinemia of infancy. J Pediatr Surg 1986;21(11):9756.

Genetic Syndromic I mmuno defic iencies with Antib ody Defe c ts

Jeffrey E. Ming, MD, PhDa, E. Richard Stiehm, MDb,*
KEYWORDS  Immunodeficiencies  Genetic syndromes  Immunoglobulin  Antibody  Hypogammaglobulinemia

In this article we review the major syndromic immunodeficiencies with significant antibody defects, many of which may require intravenous immunogammaglobulin (IVIG) therapy. We define syndromic immunodeficiency as an illness associated with a characteristic group of phenotypic abnormalities or laboratory features that comprise a recognizable syndrome. Many are familial with a defined inheritance pattern. Immunodeficiency may not be a major part of the illness and may not be present in all patients; thus, these conditions differ from primary immunodeficiency syndromes, in which immune abnormalities are a consistent and prominent feature of their disease. Certain well-recognized primary inmmunodeficiencies, such as Wiskott-Aldrich syndrome and ataxia-telangiectasia, fit into primary and syndromic immunodeficiency categories because they have characteristic organ dysfunction or dysmorphology unrelated to the immune system and a consistent, well-defined immunodeficiency.1,2 They are not discussed in this article because they have been covered in detail elsewhere.13 The immune defects of syndromic deficiencies may include B-cell (antibody), T-cell (cellular), phagocytic cell, complement, or innate immune defects or a combination of thereof. All of the illnesses mentioned in this article have antibody deficiency as the main portion or a significant portion of their immune abnormalities. A more complete discussion of all of the syndromic inmmunodeficiencies is available elsewhere.4 The inheritance pattern of each condition and the chromosomal location of the disease-related genes, when known, are indicated in the Tables 15. Online mendelian inheritance in man (OMIM)5 numbers are indicated within parentheses in the text.

Division of Human Genetics, Department of Pediatrics, The Childrens Hospital of Philadelphia, The University of Pennsylvania School of Medicine, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA b Division of Immunology/ Allergy/ Rheumatology, Mattel Childrens Hospital at UCLA, 10833 Le Conte Avenue, 22-387 MDCC, Los Angeles, CA 90095, USA * Corresponding author. E-mail address: estiehm@mednet.ucla.edu (E.R. Stiehm). Immunol Allergy Clin N Am 28 (2008) 715736 doi:10.1016/j.iac.2008.06.007 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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Table 1 Syndromic immunodeficiencies associated with growth deficiency Name Disproportionate short stature Schimke immunoosseous dysplasia Short-limb skeletal dysplasia with immunodeficiency AR 2q34-q36 Spondyloepiphyseal dysplasia, progressive nephropathy, episodic lymphopenia, pigmentary skin changes Short-limb skeletal dysplasia, metaphyseal dysplasia; may be associated with adenosine deaminase deficiency or Omenn syndrome; heterogeneous Spondyloepiphyseal dysplasia, retinal dystrophy Spondylometaphyseal dysplasia, autoimmune conditions Defects in growth hormone synthesis or sensitivity deficiency, sinopulmonary infections Long palpebral fissures, prominent eyelashes, skeletal anomalies, congenital heart disease; increased risk of autoimmune diseases Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness Broad thumbs and halluces, prominent nasal septum below ala nasi, cryptorchidism, mental retardation T, B 1111 Inheritance (Chromosome) Associated Features Immune Defect Frequency of IDa

AR

T, B

1111

Roifman syndrome Roifman-Costa syndrome Growth hormone pathway defects Kabuki syndrome

XL AR Various

B B, T B, T, NK

1111 1111 1

AD

111

CHARGE association

T, B

Rubinstein-Taybi syndrome

AD (16p13)

T, B

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; B, B-cell defect; ID, immunodeficiency; NK, NK cell defect; Ph, phagocyte defect; T, T-cell defect; XL, X-linked. a Frequency of ID: 1, < 5% of reported cases with documented ID; 11, 5%30%; 111, 30%65%; 1111 , > 65%.

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SYNDROMES ASSOCIATED WITH GROWTH DEFICIENCY Primary Immunodeficiencies Associated with Short Stature Schimke immune-osseous dysplasia

This condition (OMIM 242900) is associated with short stature with exaggerated lumbar lordosis, spondyloepiphyseal dysplasia, defective cellular immunity, and progressive renal failure (see Table 1).6,7 Patients may develop glomerulosclerosis and progress to end-stage renal disease; arteriopathy with cerebral infarcts or ischemia may be seen. Mutations in the gene encoding the chromatin remodeling protein SMARCAL1 have been detected in affected patients.8 Patients are prone to viral and bacterial infections and demonstrate decreases in CD4 T-cell numbers, mitogen-induced proliferation, and delayed cutaneous hypersensitivity responses. Immunoglobulin levels are often abnormal.7,9

Other Immunodeficiencies Associated with Short Stature Roifman syndrome (Roifman syndrome 1)

Five boys from four families had microcephaly, growth retardation, spondyloepiphyseal dysplasia, developmental delay, and retinal dystrophy (OMIM 300258).10,11 They had low or absent antibody titers in response to infection, decreased isohemagglutinins, and decreased mitogenic response to Staphylococcus aureus Cowan A. T-cell numbers and function were normal. They had epiphyseal dysplasia of the hips and long bones and vertebral anomalies. Because all reported patients have been male, X-linked recessive inheritance has been suggested.
Roifman-Costa syndrome (Roifman syndrome 2)

Four patients, including two siblings of first cousin parents, with spondylometaphyseal dysplasia, autoimmune conditions, combined immunodeficiency (low specific antibody titers, T-cell mitogenic response, and CD4 T-cell count), and recurrent infections were described (OMIM 607944).12 A boy born to a consanguineous couple had spondylometaphyseal dysplasia, decreased CD4 and CD8 T-cell numbers, recurrent infections, disseminated herpes zoster, and autoimmune disease.13 Similarity in clinical features with spondyloenchondrodysplasia (OMIM 27155) has been noted.14
Growth hormone pathway defects

Patients with defects in the growth hormone pathway and immunodeficiency have been described. In patients with growth hormone deficiency with X-linked agammaglobulinemia (OMIM 307200), individuals have recurrent sinopulmonary infections, short stature, and decreased growth hormone levels without other endocrinologic abnormalities.15 B-cell number and immunoglobulin levels are greatly decreased or absent, consistent with X-linked agammaglobulinemia. T-cell numbers and function are normal. Mutations in the gene BTK, the gene associated with isolated X-linked agammaglobulinemia, have been detected in somebut not allpatients with growth hormone deficiency and X-linked agammaglobulinemia.1618 Additional immune defects reported in association with isolated growth hormone deficiency include combined immunodeficiency,19,20 decreased natural killer (NK) cell activity,21 and hypogammaglobulinemia.22 Most children with growth hormone deficiency do not display an increased susceptibility to infection, however.23,24 Some patients with growth hormone insensitivity were found to have a mutation in the STAT5B gene. One of the patients who had recurrent skin and respiratory infections had T-cell lymphopenia and low NK and CD4 T-cell numbers.25 Both growth hormone and interleukin-2 receptor signaling use Stat5 proteins in their pathways.

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Table 2 Syndromic immunodeficiencies associated with specific organ dysfunction Name Gastrointestinal Familial intestinal polyatresia Trichohepatoenteric syndrome AR AR Multiple atresias from pylorus to rectum Severe infantile diarrhea, hepatic cirrhosis, Trichorrhxis nodosa, characteristic facies Erythematous dermatitis, eosinophilia, lymphadenopathy, hemophagocytosis; severe combined immunodeficiency Partial albinism, frequent pyogenic infections, lymphohistiocytosis, episodic thrombocytopenia Alopecia, hypo/anhydrosis, tooth anomalies, hypogammaglobulinemia Warts, hypogammaglobulinemia, infection, myelokathexis Erythematous vesiculobullous eruptions, central nervous system involvement, swirling macules of hyperpigmentation T, B B, Ph 11 1111 Inheritance (Chromosome) Associated Features Immune Defect Frequency of IDa

Dermatologic Omenn syndrome AR (11p13) T, B 1111

Griscelli syndrome, type 2

AR (15q21)

T, B, NK, Ph

1111

Hypohydrotic/anhidrotic ectodermal dysplasia with immunodeficiency WHIM syndrome Incontinentia pigmenti

XL (Xq28)

T, B

1111

AD XL (Xq28)

T, B, Ph T, B, Ph

1111 1

OLEDAID syndrome Dyskeratosis congenita

XL (Xq28) XL, AR, AD (Xq28)

Anhidrotic ectodermal dysplasia, osteopetrosis, lymphedema Atrophy and pigmentation of skin, nail dystrophy, leukoplakia of oral mucosa; risk of cancer of the mouth, anus, skin Vesiculobullous dermatitis, alopecia, diarrhea; caused by zinc deficiency, may be associated with opportunistic infections Trichorrhexis invaginata (bamboo hair), ichthyosiform dermatitis, atopic diathesis, skin infections Myotonia, muscle wasting, cataract, hypogonadism, cardiac arrhythmia; caused by triplet repeat expansion Cerebellar hypoplasia, absent corpus callosum, microcephaly, growth failure, pancytopenia, fungal sepsis

B T, B, Ph

1111 (2 cases) 11

Acrodermatitis enteropathica

AR (8q24)

T, B, Ph

11

Netherton syndrome

AR (5q32)

T, B, Ph

11

Neurologic Myotonic dystrophy AD (19q13, 3q) B 11

Hyeraal-Hreidarsson syndrome

XL (Xq28)

T, B, Ph

1111

Genetic Syndromic Immunodeficiencies

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; B, B-cell defect; ID, immunodeficiency; NK, NK cell defect; Ph, phagocyte defect; T, T-cell defect; XL, X-linked. a Frequency of immunodeficiency: 1, < 5% of reported cases with documented ID; 11, 5%30%; 111, 30%65%; 1111, > 65%.

719

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Table 3 Inborn errors of metabolism associated with immunodeficiency Name Congenital disorders of glycosylation, Types Ia, Ig, Ik Inheritance (Chromosome) Various Associated Features Decreased glycosylation, hypotonia, poor growth, other organ systems may be involved depending on the type Methylmalonic, propionic, and isovaleric acidemias, acidosis, vomiting, ketosis Dibasic aminoaciduria, hepatomegaly, failure to thrive, severe varicella infection Immune Defect B, Ph Frequency of IDa 11

Branched chain amino acidemias

AR (various)

T, B, Ph

111

Lysinuric protein intolerance

AR (14q11)

T, B, Ph, NK

111

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; B, B-cell defect; ID, immunodeficiency; NK, NK cell defect; Ph, phagocyte defect; T, T-cell defect; XL, X-linked. a Frequency of ID: 1, < 5% of reported cases with documented ID; 11, 5%30%; 111, 30% 65%; 1111, > 65%.

Table 4 Syndromes associated with chromosomal instability and/or defective DNA repair Name Nijmegen breakage syndrome Inheritance (Chromosome) AR (8q21) Associated Features Microcephaly, mental retardation, prenatal onset short stature, bird-like facies, malignancy (lymphoma), sinopulmonary and urinary tract infections Short stature, telangiectatic erythema of face, sensitivity to sunlight, pneumonia, otitis media, risk for leukemia/lymphoma Mental retardation, chromosomal instability, facial dysmorphism; sinopulmonary, gastrointestinal, cutaneous infections Immune Defect T, B Frequency of IDa 1111

Bloom syndrome

AR (15q26)

T, B, NK

111

ICF syndrome

AR (20q11)

T, B

1111

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; B, B-cell defect; ICF, immunodeficiency, centromeric instability, facial anomalies; ID, immunodeficiency; NK, NK cell defect; Ph, phagocyte defect; T, T-cell defect; XL, X-linked. a Frequency of ID: 1, < 5% of reported cases with documented ID; 11, 5%30%; 111, 30% 65%; 1111, > 65%.

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721

Table 5 Syndromes associated with chromosomal abnormalities of number or structure Name Trisomy 21 (Down syndrome) Associated Features Hypotonia, flat facies, upslanting palpebral fissures, mental retardation, sinopulmonary infections, risk of leukemia, autoimmune thyroiditis Immune Defect Frequency of IDa

T, B, Ph, NK 11

Deletion of short Growth and developmental deficiency, Greek helmet- like facies, arm of chromosome 4 (4p16) (Wolf-Hirschhorn microcephaly, coloboma, respiratory syndrome) infections Missing or abnormal X chromosome (Turner syndrome; XO, isoX, ring X)

111

Short stature, webbed neck, broad chest, T, B ovarian dysgenesis, congenital lymphedema, pulmonary/ear infections, autoimmune disease (eg, thyroid disease, celiac disease, arthritis), gonadoblastoma (if Y chromosome material present)

11

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; B, B-cell defect; ID, immunodeficiency; NK, NK cell defect; Ph, phagocyte defect; T, T-cell defect; XL, X-linked. a Frequency of ID: 1, < 5% of reported cases with documented ID; 11, 5%30%; 111, 30% 65%; 1111, > 65%.

Kabuki syndrome

This syndrome (OMIM 147920) features short stature, congenital heart disease, developmental delay, skeletal anomalies, and cleft palate.26,27 The distinctive facial features include long palpebral fissures with eversion of the lower lateral eyelid, prominent eyelashes, and abnormal ears. Frequent infections occur in approximately 60% of patients.28 Hypogammaglobulinemia, including decreased IgG and low IgA, is a common manifestation.29,30 Autoimmune conditions, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and hypothyroidism, also have been reported and may reflect the underlying immune dysfunction.31,32
CHARGE association

The abnormalities (OMIM 214800) that comprise the CHARGE association include coloboma, heart defects, atresia of the choanae, retardation of growth and development, genital hypoplasia, and ear anomalies and/or deafness.3335 Some patients who have CHARGE syndrome have been found to have mutations in CHD7.36,37 In this syndrome, asymmetric facial palsy, esophageal or laryngeal abnormalities, renal malformations, and facial clefts are present. Several patients who have CHARGE association have had immune abnormalities, including severe combined immunodeficiency with undetectable thymus tissue,38 decreased T-cell numbers and response to antigen, antibody deficiency and impaired T-cell proliferation, and isolated IgG2 deficiency.39 Patients who have CHARGE association who also have the DiGeorge anomaly and did not have a 22q11 deletion have been described.40 Other affected patients who have Di George sequence but in whom the 22q11 deletion status was not known have been reported.33,41
Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome (OMIM 180849) is characterized by broad thumbs and great toes, characteristic facial features, short stature, mental retardation, and cardiac

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abnormalities. Affected individuals have an increased susceptibility to infection. Decreased T-cell numbers, impaired delayed cutaneous hypersensitivity response,42 lymphopenia, thymic hypoplasia,43 poor response to pneumococcal vaccine,44 and a deficit in polysaccharide antibody response45 have been reported. Microdeletions and truncating mutations in the gene encoding CREB-binding protein have been detected in several affected patients.46,47 Mutations in the gene EP300, which also encodes a transcriptional coactivator, have been detected in three patients.48
Mulvihill-Smith syndrome

This disorder (OMIM 176690) is characterized by pre- and postnatal growth retardation, multiple pigmented nevi, microcephaly, reduced facial fat, genitourinary anomalies, and a high-pitched voice.49,50 Infectious complications are common, and immunodeficiency is often progressive. Impaired T-cell response to mitogen, decreased CD4 count, and low Ig levels have been described.5052
SYNDROMES ASSOCIATED WITH GASTROINTESTINAL DYSFUNCTION

Gastrointestinal abnormalities may lead to malnutrition and secondarily result in an immunodeficient state. In the syndromes described herein, however, the immunodeficiency precedes nutritional deprivation and is likely to be intrinsic to each condition (see Table 2).
Other Syndromic Immunodeficiencies Associated with Gastrointestinal Dysfunction Familial intestinal polyatresia

Multiple atretic lesions are found throughout the gastrointestinal tract in this condition (OMIM 243150). Severe combined immunodeficiency was described in three affected brothers.53 Adenosine deaminase activity was normal. The recurrent infections were not caused by the intestinal problems because they occurred while the patients still had good nutritional status. Several other cases of multiple intestinal atresia associated with immune defects have been described.5457 Two families with duodenal atresia and immunodeficiency were reported.58
Trichohepatoenteric syndrome

This condition (OMIM 222470) is characterized by severe infantile diarrhea, dysmorphic features (hypertelorism, prominent forehead, flat/broad nose), hepatic cirrhosis, and the hair abnormality of trichorrhexis nodosa. Reported immune defects have included negative skin tests with absent specific antibody response,59 pancytopenia,60 and hypogammaglobulinemia.61
SYNDROMES ASSOCIATED WITH CUTANEOUS ABNORMALITIES

Although dermatitis or skin infection often occurs in immunodeficient patients, some immunodeficiency syndromes present with primarily cutaneous manifestations (see Table 2). Some of these conditions present with alterations in pigmentation.
Primary Immunodeficiencies Associated with Cutaneous Abnormalities Griscelli syndrome

Griscelli syndrome is an autosomal recessive syndrome of partial albinism, neutropenia and thrombocytopenia, and lymphohistiocytosis (OMIM 607624).6264 Melanosomes accumulate in melanocytes, resulting in large clumps of pigment in hair shafts. Most patients suffer from recurrent and severe fungal, viral, and bacterial infections. T-cell dysfunction, hypogammaglobulinemia, and neutropenia have been reported.64 Mutations in the RAB27A gene, which encodes a GTP-binding protein of

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the Ras family, were detected in affected individuals.65 A genetically distinct form of Griscelli syndrome that is not associated with immunodeficiencies has been described.65,66
Omenn syndrome

This autosomal recessive form of familial histiocytic reticulocytosis (OMIM 267700) presents with an erythematous skin rash, eosinophilia, reticulosis, hepatosplenomegaly, protracted diarrhea, alopecia, and lymphadenopathy. A characteristic severe combined immunodeficiency leads to failure to thrive, recurrent infection, and premature death. Mutations in genes that encode any of three proteins that play a role in V(D)J recombination, RAG1, RAG2, or Artemis (DCLRE1C) can cause Omenn syndrome with SCID.67,68
WHIM syndrome

WHIM syndrome (OMIM 193670) is associated with multiple warts, hypogammaglobulinemia, infection, and myelokathexis (bone marrow retention of neutrophils).69 Neutrophil count is reduced, B-cell numbers and IgG and IgA levels are mildly decreased, and depressed T-cell numbers and diminished response to mitogen and skin tests have been noted. Mutations in the gene encoding the chemokine receptor CXCR4 were detected.70
Hypohidrotic/anhidrotic ectodermal dysplasia

A subset of patients with this form of ectodermal dysplasia has immune defects (OMIM 300291) and diminished or absent sweat glands, thin and sparse hair, and hypodontia. The subset with immune defects is genetically distinct from forms without immune defects. The most common immune defect is hypogammaglobulinemia.71,72 The X-linked recessive form is caused by mutations in the IKBKG (also termed NEMO) gene, which is involved in nuclear factor-kB regulation.71,72 An autosomal form caused by mutations in the NFKBIA gene has been described.73
Other Syndromic Immunodeficiencies Associated with Cutaneous Abnormalities Incontinentia pigmenti

Linear erythematous vesiculobullous lesions that evolve into hyperpigmented swirling macules on the trunk and proximal extremities are typical findings for this X-linked dominant neurocutaneous disorder with fetal lethality in most affected male patients (OMIM 308300). Other findings include mental retardation, seizures, alopecia, ocular abnormalities, nail dystrophy, and malformed teeth. In a review of 77 cases, 13% had significant infection, and 4 died of infectious causes.74 No consistent immunologic abnormality has been detected, but decreased neutrophil chemotaxis and impaired proliferative response to phytohemagglutinin have been described.75,76 A girl had transient immunodeficiency that resolved, likely because of progressive selection against cells carrying an active mutated X chromosome.77 Mutations in the gene IKBKG, also termed NEMO, cause incontinentia pigmenti.78 The protein is involved in the regulation of the transcriptional regulator nuclear factor-kB. Mutations in this gene cause other forms of ectodermal dysplasia associated with immune defects: hypohidrotic ectodermal dysplasia and immunodeficiency, a primary immunodeficiency, and OLEDAID syndrome (see following discussion).
OLEDAID syndrome

Two male patients with osteopetrosis, lymphedema, ectodermal dysplasia, anhidrotic type, and immune deficiency (OLEDAID, OMIM 300301), were born from mothers with mild incontinentia pigmenti.72 Both had multiple infections and died from infectious

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causes. The inflammatory response was poor, and isohemagglutinin titers and titers to Pneumococcus (despite documented infection) were decreased. Both patients had a mutation converting a stop codon to a tryptophan in IKBKG.72
Dyskeratosis congenita

Dyskeratosis congenita (OMIM 305000) is an X-linked disorder marked by reticulate skin pigmentation, nail dystrophy, leukoplakia of the oral mucosa, aplastic anemia, and an increased risk of malignancy. Progressive bone marrow failure develops in most patients and is the major cause of early mortality. Neutropenia occurs in most patients, and humoral and cellular immune responses may be defective.79,80 Thymic aplasia was reported in two patients.81 The gene that causes dyskeratosis congenita (DKC1) codes for a protein that is predicted to function in ribosome formation.82 Mutations in this gene also cause Hyeraal-Hreidarsson syndrome (see later discussion). A less common autosomal dominant form has been described (OMIM 127550) and can be caused by mutations in TERC,83 TERT,84 or TINF2.85 These gene products are involved with telomere regulation.
Acrodermatitis enteropathica

Acrodermatitis enteropathica (OMIM 201100), an autosomal recessive disorder characterized by diarrhea, dermatitis, and alopecia, is caused by inadequate zinc metabolism. Severe infection with opportunistic pathogens occurs frequently, and recurrent infection occurs in 30% of cases.86 Decreased response to phytohemagglutinin and abnormal delayed cutaneous hypersensitivity skin response are typical.87 Hypogammaglobulinemia and defective chemotaxis of neutrophils and monocytes are variably present.86,88 Clinical and immunologic abnormalities resolve after normalization of serum zinc levels. Mutations in the gene encoding the intestinal zinc transporter SLC39A4 have been detected.89
Netherton syndrome

The triad of trichorrhexis (brittle bamboo hair), ichthyosiform erythroderma, and atopic diathesis make up Netherton syndrome (OMIM 256500), an autosomal recessive disorder. Recurrent infections occur in 28% of patients, most commonly involving the skin.90,91 IgG abnormalities (hypo- and hyper-IgG) are present in 12% to 14% of patients. Impairment of delayed cutaneous hypersensitivity response, mitogen response, and neutrophil phagocytosis can occur. Increased IgE is found in 10%.92 Mutations in the gene SPINK5, which encodes a serine protease inhibitor, have been detected in affected patients.93
Syndromes Associated with Neurologic Dysfunction

Neurologic abnormalities ranging from structural abnormalities to epilepsy or ataxia have been reported in association with immunodeficiency (see Table 2).
Myotonic Dystrophy

This autosomal dominant condition (OMIM 160900) is a multisystem disorder characterized by difficulty in relaxing a contracted muscle. Muscle weakness and wasting, cataracts, hypogonadism, and cardiac conduction defects are also frequent manifestations. Cognitive function may deteriorate in adults. In the congenital form, there is severe hypotonia and respiratory insufficiency. Most cases of myotonic dystrophy are caused by a trinucleotide repeat expansion in the 30 untranslated region of the DMPK gene, which encodes the dystrophia myotonica protein kinase.9496 In general, the size of the expansion correlates with the severity of the disease and the age of onset. A large family with features typical of

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myotonic dystrophy did not have the repeat expansion in the DMPK gene 97 but had an expansion in a CCTG repeat in intron one of the ZNF9 gene.98 The most common immunologic abnormality in affected patients is a reduction in IgG level,99 although decreased IgA and IgM levels occasionally have been noted. Increased repeat length was found to correlate with decreased serum IgG level, decreased total lymphocyte count, and low T-cell numbers in one study,100 but another study found no correlation.101 There is generally no increased susceptibility to infection.102
Hyeraal-Hreidarsson Syndrome

A syndrome of X-linked cerebellar hypoplasia, psychomotor retardation, microcephaly, growth failure, and progressive pancytopenia has been reported in several affected male patients (OMIM 300240). Decreased IgG103 and death from fungal sepsis104,105 have been described. Progressive combined deficiency has been noted in other patients.106,107 This condition is caused by mutations in the DKC1 gene, the same gene that is mutated in dyskeratosis congenita.106
INBORN ERRORS OF METABOLISM ASSOCIATED WITH IMMUNODEFICIENCY Congenital Disorders of Glycosylation, Type I

Congenital disorders of glycosylation (CDG), also known as carbohydrate-deficient glycoprotein syndromes (CDGS), are autosomal recessive disorders characterized by decreased glycosylation of glycoproteins. In type I CDG, there is a defect in the production of lipid-linked oligosaccharides or their transfer to nascent proteins. Hypotonia and poor growth are present, and other organ system involvement is often present, depending on the type of CDG (see Table 3). Type Ia CDG (OMIM 212065) is caused by a defect in phosphomannomutase 2;108 abnormal fat distribution is characteristic. Severe infections often occur, and decreased IgA or IgG levels, defective response to vaccines, and diminished neutrophil chemotaxis have been observed.109 Type Ig CDG (OMIM 607143) is caused by a defect in the gene that encodes a mannosyltransferase (ALG12).110112 Microcephaly and male genital hypoplasia are characteristic. Recurrent infections and decreased IgG levels often occur.110 A short-limb skeletal dysplasia was noted in two affected siblings.113 Type Ik CDG (OMIM 608540) is caused by a defect in mannosyltransferase I (ALG1 gene);114116 refractory seizures, microcephaly, and early death are characteristic. An affected patient was noted to have decreased B-cell numbers and absence of IgG.114
Branched Chain Amino Acidurias

Three diseases that affect branched chain amino acid metabolism are associated with leukopenia: methylmalonic acidemia (OMIM 251000), propionic acidemia (OMIM 232000), and isovaleric acidemia (OMIM 243500).117119 The conditions present with metabolic acidosis, lethargy, failure to thrive, and recurrent vomiting. These individuals are at increased risk for infection, which may precipitate episodes of acidosis. Decreases in B-cell numbers and immunoglobulin levels have been reported.120122
Lysinuric Protein Intolerance

This condition (OMIM 222700) is marked by defective transport of the dibasic amino acids lysine, arginine, and ornithine in the intestine and renal tubules, leading to decreased levels of these substances in the blood, hyperammonemia, protein intolerance, and failure to thrive. Decreases in CD4 T-cell numbers,123 lymphopenia,124 IgG subclass deficiency and poor humoral response to vaccination,125 and leukopenia

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with decreased leukocyte phagocytic activity126 have been reported. Varicella infection may be severe.127
SYNDROMES WITH CHROMOSOME INSTABILITYAND/OR DEFECTIVE DNA REPAIR ASSOCIATED WITH IMMUNODEFICIENCY

Syndromes associated with chromosome instability often have immune abnormalities, and such patients are often at increased risk for malignancy (see Table 4).
Primary Immunodeficiencies Associated with Chromosome Instability and/or Defective DNA Repair Nijmegen breakage syndrome

Patients who have Nijmegen breakage syndrome (OMIM 251260) have short stature, microcephaly, and bird-like facies.128 Characteristic facial features include a receding forehead, prominent midface with a long nose, large ears, and micrognathia. Mental retardation may occur. There is an increased risk of malignancy, especially lymphoma. Cells from patients who have Nijmegen breakage syndrome are sensitive to ionizing irradiation. Bronchopneumonia and urinary tract infections commonly occur, and there is an increased risk of otitis media, mastoiditis, and sinusitis. Patients generally have abnormal immunoglobulin levels, most commonly including IgG (especially IgG2 and IgG4), and may have agammaglobulinemia.129 Reduced CD31 and CD41 cell numbers with a decreased CD4/CD8 ratio have been noted. A markedly decreased proliferative response to T-cell mitogens was noted in 94% of patients. Mutations in the NBS1 gene (also termed Nibrin or p95), which encodes a subunit of the Rad50/ Mre11 protein complex involved in double-stranded break repair, were detected in patients who have Nijmegen breakage syndrome.130,131
Bloom syndrome

This autosomal recessive condition (OMIM 210900) is characterized by growth failure, hypersensitivity to sunlight, and characteristic facial features (malar hypoplasia, micrognathia, and prominent ears). Neoplasia, especially leukemia and lymphoma, is greatly increased and is the most frequent cause of death.132 The diagnosis may be established by the finding of an increased number of sister chromatid exchanges in cells grown in medium with bromo-deoxyuridine. There is an increased susceptibility to infection, especially pneumonia and otitis media. Immunologic defects may involve humoral and cellular responses.133 The product of the BLM gene encodes a RecQ DNA helicase that is involved in DNA duplex unwinding and may interact with topoisomerases or other proteins involved in DNA repair.134
Other Syndromic Immunodeficiencies Associated with Chromosome Instability and/or Defective DNA Repair Immunodeficiency, centromeric instability, and facial anomalies syndrome

This autosomal recessive condition (ICF, OMIM 242860) is comprised of immunodeficiency, centromeric instability (involving chromosomes 1 and 16, often 9, rarely 2 and 10), and facial anomalies (ocular hypertelorism, flat nasal bridge).135,136 Mental retardation is frequent. Deletions, breaks, interchanges between homologous and nonhomologous chromosomes, and multibranched configurations involving pericentric heterochromatin have been described. The ICF syndrome differs from many other chromosome instability syndromes in that no hypersensitivity to clastogenic agents has been demonstrated; hence, it is not a chromosome breakage syndrome. Severe chronic sinopulmonary, gastrointestinal, and cutaneous infections occur. Generally, at least two immunoglobulin classes are affected in each patient.136,137

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Immunoglobulin supplementation can improve the course of the disease;138 T-cell numbers and lymphoproliferative response to mitogen may be decreased.137,139 Mutations in the gene encoding the DNA methyltransferase DNMT3B have been identified;140,141 however, other patients diagnosed with ICF with centromeric instability of chromosomes 1 and 16 do not have identified DNMT3B mutations.142,143 Of note, the patient reported by Braegger and colleagues144 (OMIM 243340) with intrauterine growth deficiency, ischiadic hypoplasia, microcephaly, renal dysfunction, cryptorchidism, postaxial polydactyly, and hypogammaglobulinemia was subsequently diagnosed with ICF.142
SYNDROMES ASSOCIATED WITH CHROMOSOMAL ABNORMALITIES OF NUMBER OR STRUCTURE Trisomy 21

Down syndrome (OMIM 190685) results from trisomy 21 and is associated with mental retardation, cardiac defects, gastrointestinal abnormalities, leukemia, and early-onset Alzheimer disease. Affected individuals can experience significant morbidity and mortality because of infections, especially respiratory infections (see Table 5).145 Although most individuals do not have clear immune dysfunction, several immunologic abnormalities have been noted. B lymphocyte counts are often low throughout childhood, and the T lymphocyte count may be low in the first 15 months of life, although these counts may normalize with time.146 No relationship between the lymphocyte subpopulation sizes and the frequency of infections was detected. Decreased B-cell numbers and low specific antibody response have been reported.145,147 Proliferation in response to phytohemagglutinin and alloantigens, delayed cutaneous hypersensitivity response, and T-cellmediated killing is variably reduced.145,148 Total NK cell number is increased but the activity is decreased.148,149 Phagocyte number is normal, but chemotaxis and oxidative metabolismand hence killingare impaired.150 There is an increased incidence of autoimmune conditions.151 Proliferation and interleukin-2 production in response to phytohemagglutinin were decreased in adult men who had Down syndrome.152
Partial Deletions of Chromosome 4p

Patients with partial deletions of chromosome 4p or Wolf-Hirschhorn syndrome (OMIM 194190) have prenatal-onset growth deficiency, mental retardation, microcephaly, ocular hypertelorism, coloboma of the iris, and seizures.153 The critical region has been narrowed to 165 kb on 4p16.3,154 and a second critical region has been proposed.155 Patients have frequent episodes of respiratory infections, partly because of recurrent aspiration, but antibody deficiencies are also common. Immune defects include common variable immunodeficiency, IgA and IgG2 subclass deficiency, IgA deficiency, and impaired polysaccharide responsiveness.156 T-cell immunity is normal. Immunodeficiency does not seem to correlate with deletion size, and all of these patients were deleted for the 4p16.3 critical region. This region likely contains a gene or genes critical for B-cell function.
Turner Syndrome

Patients with a missing or structurally abnormal X chromosome often present with short stature, shield chest, congenital lymphedema, and ovarian dysgenesis. The syndrome is associated with an increased risk for upper respiratory and ear infections, autoimmunity, and occasional neoplasia. IgG, IgM, and IgA levels may be abnormal.157 Decreased T-cell numbers with poor response to phytohemagglutinin, absent delayed cutaneous hypersensitivity reactions, and common variable immunodeficiency

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occasionally occur.158161 The relationship, if any, between the immune defects in Turner syndrome and the X-linked primary immunodeficiencies is unknown.
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78. Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 2000;405:46672. 79. Solder B, Weiss M, Jager A, et al. Dyskeratosis congenita: multisystemic disorder with special consideration of immunologic aspects. A review of the literature. Clin Pediatr (Phila) 1998;37:52130. 80. Dokal I. Dyskeratosis congenita in all its forms. Br J Haematol 2000;110:76879. 81. Trowbridge AA, Sirinavin C, Linman JW. Dyskeratosis congenita: hematologic evaluation of a sibship and review of the literature. Am J Hematol 1977;3:14352. 82. Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998;19:328. 83. Vulliamy T, Marrone A, Goldman F, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001;413:4325. 84. Armanios M, Chen JL, Chang YP, et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A 2005;102:159604. 85. Savage SA, Giri N, Baerlocher GM, et al. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 2008;82:5019. 86. Van Wouwe JP. Clinical and laboratory diagnosis of acrodermatitis enteropathica. Eur J Pediatr 1989;149:28. 87. Oleske JM, Westphal ML, Shore S, et al. Zinc therapy of depressed cellular immunity in acrodermatitis enteropathica: its correction. Am J Dis Child 1979;133: 9158. 88. Weston WL, Huff JC, Humbert JR, et al. Zinc correction of defective chemotaxis in acrodermatitis enteropathica. Arch Dermatol 1977;113:4225. 89. Kury S, Dreno B, Bezieau S, et al. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet 2002;31:23940. 90. Greene SL, Muller SA. Nethertons syndrome: report of a case and review of the literature. J Am Acad Dermatol 1985;13:32937. 91. Stryk S, Siegfried EC, Knutsen AP. Selective antibody deficiency to bacterial polysaccharide antigens in patients with Netherton syndrome. Pediatr Dermatol 1999;16:1922. 92. Smith DL, Smith JG, Wong SW, et al. Nethertons syndrome: a syndrome of elevated IgE and characteristic skin and hair findings. J Allergy Clin Immunol 1995; 95:11623. 93. Chavanas S, Bodemer C, Rochat A, et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 2000;25:1412. 94. Brook JD, McCurrach ME, Harley HG, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 30 end of a transcript encoding a protein kinase family member. Cell 1992;68:799808. 95. Mahadevan M, Tsilfidis C, Sabourin L, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 30 untranslated region of the gene. Science 1992; 255:12535. 96. Fu YH, Pizzuti A, Fenwick RG Jr, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 1992;255:12568. 97. Ranum LP, Rasmussen PF, Benzow KA, et al. Genetic mapping of a second myotonic dystrophy locus. Nat Genet 1998;19:1968. 98. Liquori CL, Ricker K, Moseley ML, et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 2001;293:8647.

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99. Wochner RD, Drews G, Strober W, et al. Accelerated breakdown of immunoglobulin G (IgG) in myotonic dystrophy: a hereditary error of immunoglobulin catabolism. J Clin Invest 1966;45:3219. 100. Nakamura A, Kojo T, Arahata K, et al. Reduction of serum IgG level and peripheral T-cell counts are correlated with CTG repeat lengths in myotonic dystrophy patients. Neuromuscul Disord 1996;6:20310. 101. Pan-Hammarstrom Q, Wen S, Ghanaat-Pour H, et al. Lack of correlation between the reduction of serum immunoglobulin concentration and the CTG repeat expansion in patients with type 1 dystrophia correction of Dystrofia myotonica. J Neuroimmunol 2003;144:1004. 102. Suzumura A, Yamada H, Matsuoka Y, et al. Immunoglobulin abnormalities in patients with myotonic dystrophy. Acta Neurol Scand 1986;74:1329. 103. Hoyeraal HM, Lamvik J, Moe PJ. Congenital hypoplastic thrombocytopenia and cerebral malformations in two brothers. Acta Paediatr Scand 1970;59:18591. 104. Hreidarsson S, Kristjansson K, Johannesson G, et al. A syndrome of progressive pancytopenia with microcephaly, cerebellar hypoplasia and growth failure. Acta Paediatr Scand 1988;77:7735. 105. Berthet F, Caduff R, Schaad UB, et al. A syndrome of primary combined immunodeficiency with microcephaly, cerebellar hypoplasia, growth failure and progressive pancytopenia. Eur J Pediatr 1994;153:3338. 106. Knight SW, Heiss NS, Vulliamy TJ, et al. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. Br J Haematol 1999;107:3359. 107. Sznajer Y, Baumann C, David A, et al. Further delineation of the congenital form of X-linked dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome). Eur J Pediatr 2003;162:8637. 108. Matthijs G, Schollen E, Pardon E, et al. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet 1997;16:8892. 109. Blank C, Smith LA, Hammer DA, et al. Recurrent infections and immunological dysfunction in congenital disorder of glycosylation Ia (CDG Ia). J Inherit Metab Dis 2006;29:592. 110. Chantret I, Dupre T, Delenda C, et al. Congenital disorders of glycosylation type Ig is defined by a deficiency in dolichyl-P-mannose:Man7GlcNAc2-PP-dolichyl mannosyltransferase. J Biol Chem 2002;277:2581522. 111. Grubenmann CE, Frank CG, Kjaergaard S, et al. ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg. Hum Mol Genet 2002;11: 23319. 112. Thiel C, Schwarz M, Hasilik M, et al. Deficiency of dolichyl-P-Man:Man7GlcNAc2-PP-dolichyl mannosyltransferase causes congenital disorder of glycosylation type Ig. Biochem J 2002;367:195201. 113. Kranz C, Basinger AA, Gucsavas-Calikoglu M, et al. Expanding spectrum of congenital disorder of glycosylation Ig (CDG-Ig): Sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality. Am J Med Genet A 2007;143:13718. 114. Kranz C, Denecke J, Lehle L, et al. Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I. Am J Hum Genet 2004;74:54551. 115. Grubenmann CE, Frank CG, Hulsmeier AJ, et al. Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik. Hum Mol Genet 2004;13:53542.

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116. Schwarz M, Thiel C, Lubbehusen J, et al. Deficiency of GDP-Man:GlcNAc2PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik. Am J Hum Genet 2004;74:47281. 117. Matsui SM, Mahoney MJ, Rosenberg LE. The natural history of the inherited methylmalonic acidemias. N Engl J Med 1983;308:85761. 118. Muller S, Falkenberg N, Monch E, et al. Propionic acidaemia and immunodeficiency. Lancet 1980;1:5512. 119. Kelleher JF, Yudkoff M, Hutchinson R, et al. The pancytopenia of isovaleric acidemia. Pediatrics 1980;65:10237. 120. Church JA, Koch R, Shaw KN, et al. Immune functions in methylmalonicaciduria. J Inherit Metab Dis 1984;7:124. 121. Wong SN, Low LC, Lau YL, et al. Immunodeficiency in methylmalonic acidaemia. J Paediatr Child Health 1992;28:1803. 122. Raby RB, Ward JC, Herrod HG. Propionic acidaemia and immunodeficiency. J Inherit Metab Dis 1994;17:2501. 123. Dionisi-Vici C, De Felice L, el Hachem M, et al. Intravenous immune globulin in lysinuric protein intolerance. J Inherit Metab Dis 1998;21:95102. 124. Nagata M, Suzuki M, Kawamura G, et al. Immunological abnormalities in a patient with lysinuric protein intolerance. Eur J Pediatr 1987;146:4278. 125. Lukkarinen M, Parto K, Ruuskanen O, et al. B and T cell immunity in patients with lysinuric protein intolerance. Clin Exp Immunol 1999;116:4304. 126. Yoshida Y, Machigashira K, Suehara M, et al. Immunological abnormality in patients with lysinuric protein intolerance. J Neurol Sci 1995;134:17882. 127. Lukkarinen M, Nanto-Salonen K, Ruuskanen O, et al. Varicella and varicella immunity in patients with lysinuric protein intolerance. J Inherit Metab Dis 1998;21:10311. 128. van der Burgt I, Chrzanowska KH, Smeets D, et al. Nijmegen breakage syndrome. J Med Genet 1996;33:1536. 129. Group. Nijmegen breakage syndrome: the International Nijmegen Breakage Syndrome Study Group. Arch Dis Child 2000;82:4006. 130. Matsuura S, Tauchi H, Nakamura A, et al. Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet 1998;19:17981. 131. Varon R, Vissinga C, Platzer M, et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 1998;93:46776. 132. German J. Blooms syndrome: the first 100 cancers. Cancer Genet Cytogenet 1997;93:1006. 133. Kondo N, Motoyoshi F, Mori S, et al. Long-term study of the immunodeficiency of Blooms syndrome. Acta Paediatr 1992;81:8690. 134. Ellis NA, Groden J, Ye TZ, et al. The Blooms syndrome gene product is homologous to RecQ helicases. Cell 1995;83:65566. 135. Tiepolo L, Maraschio P, Gimelli G, et al. Multibranched chromosomes 1, 9, and 16 in a patient with combined IgA and IgE deficiency. Hum Genet 1979;51: 12737. 136. Maraschio P, Zuffardi O, Dalla Fior T, et al. Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: the ICF syndrome. J Med Genet 1988;25:17380. 137. Smeets DF, Moog U, Weemaes CM, et al. ICF syndrome: a new case and review of the literature. Hum Genet 1994;94:2406. 138. Hagleitner MM, Lankester A, Maraschio P, et al. Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). J Med Genet 2008;45:939.

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139. Fasth A, Forestier E, Holmberg E, et al. Fragility of the centromeric region of chromosome 1 associated with combined immunodeficiency in siblings. A recessively inherited entity? Acta Paediatr Scand 1990;79:60512. 140. Okano M, Bell DW, Haber DA, et al. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99:24757. 141. Xu GL, Bestor TH, Bourchis D, et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 1999;402:18791. 142. Kloeckener-Gruissem B, Betts DR, Zankl A, et al. A new and a reclassified ICF patient without mutations in DNMT3B and its interacting proteins SUMO-1 and UBC9. Am J Med Genet A 2005;136:317. 143. Jiang YL, Rigolet M, Bourchis D, et al. DNMT3B mutations and DNA methylation defect define two types of ICF syndrome. Hum Mutat 2005;25:5663. 144. Braegger C, Bottani A, Halle F, et al. Unknown syndrome: ischiadic hypoplasia, renal dysfunction, immunodeficiency, and a pattern of minor congenital anomalies. J Med Genet 1991;28:569. 145. Ugazio AG, Maccario R, Notarangelo LD, et al. Immunology of Down syndrome: a review. Am J Med Genet Suppl 1990;7:20412. 146. de Hingh YC, van der Vossen PW, Gemen EF, et al. Intrinsic abnormalities of lymphocyte counts in children with Down syndrome. J Pediatr 2005;147:7447. 147. Lockitch G, Singh VK, Puterman ML, et al. Age-related changes in humoral and cell-mediated immunity in Down syndrome children living at home. Pediatr Res 1987;22:53640. 148. Montagna D, Maccario R, Ugazio AG, et al. Cell-mediated cytotoxicity in Down syndrome: impairment of allogeneic mixed lymphocyte reaction, NK and NK-like activities. Eur J Pediatr 1988;148:537. 149. Cossarizza A, Monti D, Montagnani G, et al. Precocious aging of the immune system in Down syndrome: alteration of B lymphocytes, T-lymphocyte subsets, and cells with natural killer markers. Am J Med Genet Suppl 1990;7:2138. 150. Barroeta O, Nungaray L, Lopez-Osuna M, et al. Defective monocyte chemotaxis in children with Downs syndrome. Pediatr Res 1983;17:2925. 151. Cuadrado E, Barrena MJ. Immune dysfunction in Downs syndrome: primary immune deficiency or early senescence of the immune system? Clin Immunol Immunopathol 1996;78:20914. 152. Park E, Alberti J, Mehta P, et al. Partial impairment of immune functions in peripheral blood leukocytes from aged men with Downs syndrome. Clin Immunol 2000;95:629. 153. Zollino M, Di Stefano C, Zampino G, et al. Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome. Am J Med Genet 2000; 94:25461. 154. Wright TJ, Ricke DO, Denison K, et al. A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum Mol Genet 1997;6:31724. 155. Zollino M, Lecce R, Fischetto R, et al. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 2003;72:5907. 156. Hanley-Lopez J, Estabrooks LL, Stiehm R. Antibody deficiency in Wolf-Hirschhorn syndrome. J Pediatr 1998;133:1413. 157. Lorini R, Ugazio AG, Cammareri V, et al. Immunoglobulin levels, T-cell markers, mitogen responsiveness and thymic hormone activity in Turners syndrome. Thymus 1983;5:616.

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158. Cacciari E, Masi M, Fantini MP, et al. Serum immunoglobulins and lymphocyte subpopulations derangement in Turners syndrome. J Immunogenet 1981;8: 33744. 159. Donti E, Nicoletti I, Venti G, et al. X-ring Turners syndrome with combined immunodeficiency and selective gonadotropin defect. J Endocrinol Invest 1989;12: 25763. 160. Robson SC, Potter PC. Common variable immunodeficiency in association with Turners syndrome. J Clin Lab Immunol 1990;32:1436. 161. al-Attas RA, Rahi AH, Ahmed el FE. Common variable immunodeficiency with CD41 T lymphocytopenia and overproduction of soluble IL-2 receptor associated with Turners syndrome and dorsal kyphoscoliosis. J Clin Pathol 1997;50: 8769.

Histor y of I mmuno globulin Replacement

Martha M. Eibl, MD*
KEYWORDS  Immunoglobulin  IVIg treatment  Primary immunodeficiency  Antibody deficiency  Immune modulation

HISTORY OF IMMUNOGLOBULIN TREATMENT

In 1890, von Behring and Kitasato1 proved that bloodserum of rabbits immunized with tetanus toxin contained activity against tetanus poison, and such blood serum transferred to rabbits protected these normal (naive) animals against tetanus. In 1901, von Behring was awarded the first Nobel Prize in Medicine or Physiology for his work in this field. Ehrlich2 demonstrated that protection could be quantitatively correlated to the amount of antitoxin in the blood. In 1910, Dr. A. Wolff-Eisner, a 33-year-old physician in Berlin, published Curative Serum Therapy and Experimental Therapy, a handbook for clinic and medical practice.3 His intentionnot so far from our own current intentionswas to convey to clinicians and practitioners the advances of biological science as they relate to therapy. The theoretic [the science] should only be included as far as necessary for the understanding of treatment. Several infectious diseases and conditions such as allergy and cancer were treated with curative serum. Serum therapy of diphtheria and tetanus was already common practice.4 In Germany alone, five companies, including Hochster Farbwerke, Merck-Darm stadt, and Behring-Hochst, produced curative serum; products from Schering and Parke-Davis were also available. There was international cooperation: Calmette5 in Lille, France worked on the treatment of snake venom; Wolff-Eisner in Berlin concentrated on serum therapy of hay fever and treatment of bacterial diseases. Serum therapy was introduced in the treatment of staphylococcal disease (van de Velde, Holland), streptococcal infection (R. Freund, Berlin), and meningococcal disease (Flexner, New York).68 Curative (mainly antitoxic) sera were produced in different animal species because serum sickness already was recognized as one of the feared complications of therapy. Convalescent human sera had great advantages compared

Medical University of Vienna, Center for Physiology, Pathophysiology and Immunology, Institute of Immunology, Borschkegasse 8a, 1090 Vienna, Austria * Immunology Outpatient Clinic, Schwarzpanierstrasse 15/1/9, 1090 Vienna, Austria. E-mail address: martha.eibl@meduniwien.ac.at Immunol Allergy Clin N Am 28 (2008) 737764 doi:10.1016/j.iac.2008.06.004 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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with sera of immunized animals, because human serum could be applied without the risk of anaphylaxy and serum sickness. In 1907, Cenci9 (Italy) applied convalescent human sera for the prevention of measles. McKhann and Chu10 followed in the same indication with material obtained from the globulin fraction of placenta in 1933. Treatment with curative sera was performed successfully and saved the lives of many individuals in the first third of the twentieth century,5 mainly children with diphtheria and soldiers with tetanus in World War I. Treatment was also widely applied in pneumococcal disease. Although antibody treatment had been widely used,11 information on serum protein composition was incomplete until the 1930s. The proof that antibodies localized to the immunoglobulin (Ig) compartment of human serum came in the 1930s. Initially fractionation was performed by precipitation with different salt concentrations (such as ammonium sulfate). In 1938, Karelitz,12 an associate of Schick, published prophylaxis against measles with the globulin fraction of immune adult serum in The American Journal of Diseases of Children, but profound understanding on serum proteins became available only after Tiselius and Kabat13 published their pioneering work on electrophoresis of immune serum in Science in 1938. Just 2 years later, Cohn and his group14,15 reported on preparation and properties of serum and plasma proteins, which opened the way for Ig prophylaxis and treatment of infectious diseases.
Fractionation of Serum Proteins

Techniques developed by Cohn and his coworkers14,15 in Boston at the beginning of World War II led to the development of the separation of plasma proteins into individual stable fractions with different biologic functions. The basis for Cohns fractionation was to use low concentrations of alcohol by reducing the pH and lowering ionic strength. The procedure was performed at low temperature, which reduced the likelihood of contamination and made large-scale fractionation possible. This method, further refined in cooperation with J.L. Oncley,15 is basically still in use and, with some additional steps, yields Ig for intramuscular and subcutaneous use. By the mid-1940s, however, Cohn14 realized that an Ig product that could be applied intravenously was desirable. He recognized that the removal of depressor substances was necessary and would require new technology. In the following years, numerous cooperations were established between Cohn and others,16 including Elliot Robinson at the Massachusetts Antitoxin and Vaccine Laboratory, Charles Janeway17 (Sen.) and John Enders at Harvard, and clinical trials to prevent viral diseases (eg, measles and hepatitis) were initiated. Because of the limited availability of blood, Ig products were also prepared from placentas. During and after World War II, the supply of gammaglobulin increased as plasma from the American Red Cross became available. The first Ig products were mainly given to prevent and treat infections: polymyelitis, measles, mumps, pertussis, and hepatitis A.18,19 These Ig disappeared as soon as the respective diseases could be and were prevented by vaccination. Other Ig products with defined specificities were developed subsequently and continue to be used currently (eg, tetanus Ig,20 RHo(D) Ig,21 rabies Ig, hepatitis B Ig,22 and varicella zoster Ig23). Respiratory syncytial virus hyperimmunoglobulin24 was licensed but later replaced by a respiratory syncytial virus monoclonal antibody,25,26 one of the few monoclonal antibodies that made its way into clinical application in the prevention of an infectious diseasepneumonia caused by respiratory syncytial virus, a dangerous, potentially fatal disease in premature infants and newborns.

History of Immunoglobulin Replacement

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Early Treatment of Primary Immunodeficiency with Immunoglobulin

The first patient who had primary immunodeficiency (PID) described by Bruton27 in 1952 had recurrent infections and multiple episodes of sepsis. Testing his serum revealed the absence of specific antibodies, and serum electrophoresis indicated that Ig were lacking. The boy was treated with subcutaneous gammaglobulin and was free of sepsis and severe infections thereafter. The clinical history of the patient indicated that in addition to life-threatening bacterial infections, he had mumps four times but managed to recover from the disease without problems or complications. That finding, which was an experiment of nature, indicated that antibodies are important to prevent the disease, but T-cell immunity is sufficient to clear this viral infection. Parallel to this observation, numerous patients with agammaglobulinemia were identified and treated by Janeway and others.17,28 In the early days, however, especially if a product had not been prepared in the cold, contamination by bacterial toxins occurred despite the fact that the product passed tests of sterility and pyrogenicity. Although Janeway17 also preferred the subcutaneous route, intramuscular administration of immune serum globulin became state-of-the-art for the years to come. Immune serum globulin became standard treatment of patients with antibody deficiency syndromes (agammaglobulinemia and hypogammaglobulinemia) in the 1950s and was widely used with this indication for at least the next two decades.2939 Its efficacy has been well documented. The products contained mainly IgG traces of IgM and differing amounts of IgA. Ig treatment substantially improved the prognosis of patients with agammaglobulinemia, hypogammaglobulinemia, and other forms of severe antibody deficiencies. The recommended dose was 25 mg/kg/wk. After the efficacy of IgG (for intramuscular use) had been clearly proven in primary immunodeficiencies in the early 1950s, the British Medical Research Council set up a working party to find the optimal dose for the treatment of patients with antibody deficiency40 (hypogammaglobulinemia). Based on the results, a 50 mg/kg/wk dose was regarded as adequate, but it was felt that the previously accepted dose of 100 mg/kg/mo might be justified in view of the discomfort the injection caused and with regard to the high expense of treatment. In 1966, Janeway17 considered a raise in serum levels of 200 mg/dL necessary to prevent invasive bacterial infections and suggested 300 mg/kg as an initial dose to be followed by 100 mg/kg/mo. Products of intramuscular Ig of different manufacturers were similar in composition and activity as long as the plasma of at least 1000 donors had been pooled. The spectrum and quality of antibodies were comparable to antibodies in the plasma of the starting material. Fc-mediated functions were preserved. Antibodies were enriched approximately 10- to 20-fold in the 15% to 18% solutions as compared with plasma. Transmission of viral diseases was a major concern because hepatitis B transmission did occur when the starting material was contaminated.4144 If the single donations of plasma were free of hepatitis B surface antigen and if appropriate fractionation methodology was used, however, the final product was proven to be safe with respect to the transmission of hepatitis B. Serum Ig for intramuscular use also had great disadvantages. The intramuscular injection was painful, maximum serum levels were not reached before 24 hours and could take several days, and in vivo recovery was usually less than 50%.45,46 At higher dosages, the preservative containing mercury caused increased concern.47,48 These products could not be given intravenously because of adverse reactions. These reactions, mainly in children, caused chills and fever but also could be severe and lead to shock and even fatal reactions.49 Adverse effects occurred in 15% to 25% or more of applications and were mainly attributed to aggregates in the product. Researchers soon recognized that reactions were more frequent

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in agammaglobulinemic patients compared with patients with normal gammaglobulin serum levels, who received these products with the aim of preventing recurrent or severe infections. Studies in patients with antibody deficiency demonstrated a reduction of acute and chronic infections by intravenous Ig (IVIg).5052 Early studies in patients with common variable immunodeficiency showed a significant reduction in infection rate as compared with before IVIg treatment.53 The superiority of IVIg to intramuscular Ig was proven by direct comparison.54,55 Ig products that could be applied intravenously were clearly desirable, and serum Ig had to be further treated to be tolerated via the IV route.
Different Intravenous Immunoglobulin Products

Several different methods have been tried to arrive at safe and efficacious preparations. Because aggregates were thought to be the main cause of adverse effects, proteolytic treatment was the first choice. Ample evidence from previous times when animal sera treated with pepsin or trypsin were used indicated that this treatment reduced reactivity. The first IVIg product from human plasma prepared by pepsin treatment, manufactured by Behringwerke in Germany, has been in clinical use since the 1960s. This product contains mainly Fab2 fragments, has no Fc-mediated activity, and has a half-life of 24 hours or less in the circulation. It was principally well tolerated, although it still has some adverse effects in immunodeficient patients. With its short half-life, however, it is clearly unsuitable for the treatment of patients with antibodydeficiency syndromes. Other subsequently developed IVIg products that could be considered for treatment of patients with primary immunodeficiency diseases were chemically and enzymatically modified preparations. Several IVIgG preparations were created in which the Ig was basically unmodified. Different methods were used to arrive at products that were safe when given intravenously and showed wide variation with respect to functional integrity (Table 1).5662 In 1979, a workshop entitled Ig: Characteristics and Uses of Intravenous Preparations was organized by J.S. Finlayson and Barbara Alving and sponsored by the Bureau of Biologics, the US Food and Drug Administration, and the National Heart, Lung and Blood Institute. The purpose of the workshop was (according to the preface by the editors) to review the international use of IVIg preparations in the treatment of immunodeficient and immunosuppressed patients, explore potential clinical uses for such preparations, discuss the nature of adverse reactions to these products, and define, insofar as possible, the ideal characteristics ofIVIg.63 The specialties of the more than 200 attending investigators ranged from basic science to manufacturing to clinical medicine. The consensus at the 1979 meeting was that IVIg products were indicated for the provision of antibodies to prevent certain infectious diseases and for the treatment of patients with antibody deficiency, primary immunodeficiencies with agammaglobulinemia and hypogammaglobulinemia, other forms of PID (eg, severe combined immunodeficiency, combined immunodeficiency), and secondary antibody deficiency.64 At the meeting, individual clinical investigators reported their experience regarding treatment with the different enzymatically, chemically modified or intact Ig products. In most cases, the number of patients in the individual groups was between 10 and 20, and there was agreement that the IV route of Ig treatment was advantageous to intramuscular therapy.65 The adverse reactions observed and reported by the different investigators were virtually identical and are described later in the article.49,6698 The conclusion was that IVIg was a promising new option in the treatment of patients

History of Immunoglobulin Replacement

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Table 1 Intravenous immunoglobulin preparations Enzymatically treated Procedure Pepsin Manufacturer Behringwerke Nikon Seiyaku Kaketsuken Plasmin Hyland Michigan Green Cross Merieux Chemically treated Procedure b propiolactone PH4 1 treated pepsin Reduced, alkylated Unmodified Procedure Si O2 QAE sephadex Ethanol DEAE sephadex stabilized with albumin DEAE sephadex PEG/HES PEG, Plasmin Treatment Salting out, PEG, isoelectric precipation Cohn II 1 III 1 PEG 4000 Ethanol, pH4 Manufacturer Condie KABI Winnipeg Armour Green Cross Immuno Continental Scottish National Blood Transfusion Service Country USA Switzerland USA USA Japan Austria Canada Great Britain Manufacturer Biotest SRC, Sandoz Cutter Country Germany Switzerland USA Country Germany Japan Japan USA USA Japan France

with humoral immunodeficiency: impaired antibody production. Adverse events often were seen, but they were manageable. The causes of those adverse events were not completely understood. At the meeting in 1979, a single presentation from Japan69 on 5406 cases of IVIg treatment for numerous diseases in the specialties of pediatrics, medicine, surgery, and neurosurgery with 82% effectiveness gave one of the early examples of an empiric approach indicating that there might be a much greater scope of treatment with IVIg than generally accepted at the time. Researchers soon realized that treatment with IgG, the only component of most IVIg products, is necessary and sufficient for the prevention of infection and the prophylaxis of acute exacerbations of lung disease (pneumonia) and sinusitis,5052,70 even in patients in whom all isotypes of Ig were absent (the agammaglobulinemics). Researchers recognized that antibody quality, especially functions mediated by the Fc portion of the antibody, were important. The question of antibody diversity was raised on several occasions before and a long time after this workshop in 1979. One of the questions raised was whether it was necessary to provide the starting material of individual products from the geographic area where the patients are.71 The current view, which is the result of a long-lasting debate, has been that as long as the number of donations is 15,000 to 60,000 per plasma pool for production, the antibody diversity in the product can

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be considered adequate.72 Selective antibodies are tested lot-wise to show that antitoxic, antiviral, and antibacterial qualities are preserved. Extended testing of current preparations proves that products have only traces of aggregates, contain 90% or more monomeric IgG, are free of vasoactive contaminants, and have proven Faband Fc-mediated antibody functions.6668
Fab and Fc Properties

The specific antibody activity, the function of antigen binding, resides in the Fab part of the Ig, and secondary functions of the Ig are carried by the Fc portion of the molecule. The Fc portion determines its isotype (eg, class and subclass). It interacts with receptors on phagocytic cells (eg, neutrophil granulocytes and macrophages) to facilitate engulfment of antibody-coated cells and pathogens. The Fc portion initiates activation of the complement cascade via the classic activation pathway by binding C1q (an early complement component). It is responsible for the active passage of Ig from mother to fetus through the placenta and determines the half-life of Ig in the circulation. The Fab and Fc regions of the Ig are connected by the hinge region of the molecule. The hinge region is flexible; its function is important for avidity, and it is the most sensitive portion of Ig with respect to chemical and enzyme treatment. Specific antibody activities are crucial for antigen recognition. Fab fragments are sufficient for toxin neutralization. Antiviral activity depends on recognition through Fab but is much more potent by the intact antibody molecule. The elimination of bacteria requires the Fab and the Fc moiety of the Ig.
Immunomodulatory Activity

Early observations by Barandun in the 1960s noted that in a patient who had primary immunodeficiency disease and hemolytic anemia, signs and symptoms of hemolysis decreased and Coombs test results normalized when treated with IVIg. Parallel to those observations, a child who had idiopathic thrombocytopenic purpura (ITP) and chicken pox was treated with IVIg, and platelet counts normalized. Subsequent to those observations, other patients with thrombocytopenia were successfully given IVIg.73 Imbach and colleagues74 followed up on these anecdotes and started clinical studies in children with acute and chronic ITP. The dose was 400 mg/kg for 5 days, and almost all patients showed a dramatic response with fast normalization of platelet counts. After the report by Imbach74 on the effect of IVIg in ITP, numerous studies confirmed these results,7582 and other studies have been conducted to investigate the effect of IVIg in different organ-specific and systemic autoimmune diseases.8395 These studies includedbut were not limited toinvestigations in the following areas: hematology (numerous), dermatology (eg, bullous pemphigoid), endocrinology (eg, thyroid dis ease, diabetes), and neurology (eg, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, intractable childhood epilepsy, myasthenia gravis). The effect of IVIg treatment in autoimmune diseases clearly depended on the Fc portion of the Ig. Although chemically modified IVIg with its Fc function mainly preserved was effective in ITP, pepsin-treated Ig, which contained only the Fab2 part of the Ig molecule, had only minimal effect.96,97 Although the mechanism of action of IVIg in different autoimmune diseases was not clear, the following hypotheses have been suggested to explain the results observed: 1. Ig binds activated complement components, solubilizes immune complexes, and inhibits their binding to target cells. Basta and coworkers98 protected guinea pigs by Ig in the complement-mediated Forssman shock and emphasized that the binding of activated complement components could be the crucial mechanism

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of the effect of IVIg in hematologic autoimmune diseases.99,100 This hypothesis became the basis of a later controlled study that demonstrated the effect of IVIg in dermatomyositis.101,102 2. Another hypothesis centered around the inhibition of the binding of antibodycoated target cells to Fc receptors on phagocytic cells: Fc receptor blockade.75,103 Based on this hypothesis, an Ig product with anti RHo(D) specificity was later licensed for the treatment of ITP.104106 An experimental study with an anti-Fc receptor monoclonal antibody proved the principle but has not been followed up as a routine mode of treatment.107,108 3. The immunomodulatory effect of IVIg was described and thought to be crucial in the down-modulation of the production of autoantibodies by B cells.109 The importance of anti-idiotypic antibodies has been emphasized.110 Anti-idiotypic antibodies are present in IVIg and antibodies to ab T-cell receptors,111 major histocompatibility complex class I,112 CD45 (Fas),113,114 and other self-determinants115 and were thought to be the effective principle in the treatment of other autoimmune diseases  (eg, myasthenia gravis, Guillain-Barre syndrome, systemic lupus erythematosus, nephritis).110,116 In addition to their specificities, anti-idiotypic antibodies are leading to Ig dimerization and the functional importance of the dimers in Fc receptor ligation, and signaling has been demonstrated.110 4. Several studies indicated that IVIg has an immunomodulatory effect, not only on B cells but also on T cells. It down-modulates not only B-cell activation but also T- and B-cell interaction and is inhibitory in mixed lymphocyte reaction and mitogen and interleukin-2induced proliferation of mononuclear cells.117 IVIg products were shown to contain antibodies against different cytokines, and these antibodies were thought to be important for the immunomodulatory effect.118 Based on the downregulation of the immune response, IVIg has been studied in bone marrow and solid organ transplantation.119123
Modulation of Inflammation by Immunoglobulin

Certain pathophysiologic events (eg, Kawasaki disease, vasculitis) are characterized by systemic, excessive inflammation. Cells and mechanisms of the innate and adaptive immunity are operational in this process. Phagocytes, B cells, and T cells are central in mounting inflammatory host response to gram-negative and -positive bacteria and their products, such as lipopolysaccharide and superantigens.124128 A deregulated release of inflammatory cytokines results in life-threatening pathology with fever and organ damage and may lead to shock and fatality. The release of inflammatory cytokines and their activity can be regulated at different levels: gene expression, translation, release, receptor expression, and neutralization of cytokine activity by antibody or soluble cytokine-binding inhibitors. IVIg has been shown to regulate the burst of inflammatory cytokines at the level of cytokine receptor interaction with antibodies against cytokines and the induction of receptor antagonists.118,129133 The effects of monomeric polymeric IgG and immune complexes on Fc receptors have been studied in several laboratories.75,134136 Clinical evidence that IVIg treatment is safe and effective in a deregulated inflammatory disease has been provided by large, controlled clinical studies of children who have Kawasaki disease, which is a disease with prolonged fever, rash, erythema of palms and soles, and mucosal inflammation with involvement of the oral pharynx and conjunctiva.137 The underlying pathology is characterized by vasculitis that involves medium and large arteries. Up to 25% of children who have this syndrome and received aspirin as the standard treatment developed coronary artery lesions with severe sequelae. High-dose IVIg (400 mg/kg on 5 consecutive days or 2 g/kg in one infusion) impressively stopped

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the inflammatory symptoms and significantly reduced the prevalence of coronary artery abnormalities to less than 5% when given early in the disease.138,139 Clinical trials were double-blind, randomized controlled studies that compared the then-standard treatment of Kawasaki disease with aspirin to aspirin plus IVIg.
Expanding the Scope of Accepted Indications in 1990

The accepted modes of action of IgG, namely provision of antibodies,140146 inhibition of Fc receptor binding (on phagocytes), down-modulation of inflammation, and downmodulation of antibody production147149 (immune response), were the basis of the consensus in 1990.140 According to the consensus of 1990, IVIg was indicated for the prevention and treatment of the following disorders: Primary immunodeficiencies Pediatric aids Bone marrow transplantation Chronic lymphocytic leukemia with hypogammaglobulinemia Idiopathic thrombocytopenic purpura Kawasaki syndrome Chronic inflammatory demyelinating polyneuropathies  Guillain-Barre syndrome Although a trial to prevent infections in premature infants was one of the first randomized trials with intramuscular Ig,150 the question whether treatment with Ig is beneficial in this vulnerable group of patients is still undecided. At the 1990 consensus meeting, large clinical trials to answer the question of efficacy of Ig in premature infants and neonates were thought to be important. A large multicenter controlled trial151 could not provide clear results for efficacy, and smaller clinical studies later came to similar conclusions.152,153 Adverse events observed in the course of high-dose treatment were of increasing concern, as was the transmission of blood-borne pathogens at that time because of the theoretic threat of possible HIV transmission by IVIg, which fortunately did not happen. Transmission of blood-borne pathogens did occur, however, in the 1990s, when hepatitis C was transmitted in clinical trials and with treatment with IVIg of patients who had PID (see the later section on adverse events). The recently developed test kits based on hepatitis C antigen produced by a recombinant technology opened the way to eliminating donations from hepatitis C antibodypositive plasma donors. Industry, in cooperation with the health authorities, reacted in a fast and proper way. By the end of the decade, all licensed products could be considered free of contaminating viral agents. In the 1990s, off-label use of IVIg started to widen for numerous autoimmune and inflammatory indications in the treatment of neurologic diseases.154156 The dose was usually 2 g/kg either in five applications of 400 mg/kg each or in two applications of 1 g/kg each. In the course of expanding high-dose treatment, rare but severe adverse events were noticed, and it became evident that although rare, they might occur in patients who had PID and were on regular replacement therapy. Although during the course of almost two decades [19902008] changes in labeled indications for IVIg treatment were minimal, more diseases have been treated off-label.
CONSENSUS STATEMENTS, 1999^2001 (EXPERT MEETINGS, NATIONAL INSTITUTES OF HEALTH, FOOD AND DRUG ADMINISTRATION, AND PUBLISHED REPORTS)

The results started to come in from studies initiated to analyze the effect of IVIg in the different areas of autoimmune disease.157,158 Studies of IVIg treatment in 53 different

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diseases from the areas of hematology, infectious disease, neurology, obstetrics, rheumatology, endocrinology,9294 and other specialties were investigated. The first studies, even when based on meta-analysis of several clinical trials, were not large enough to give clear support for additional indications, even when the results did look promising. These studies opened the way for further trials, which, almost a decade later, arrived at several indications supported by grade I evidence. Based on these results, IVIg became a generally accepted standard way of treatment by the  end of the twentieth century in numerous neurologic diseases such as Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. By 20032004, approximately 60% to 65% of IVIg had already been used for patients with neurologic disease.72,159 In 2006, a document was prepared by a committee of the American Academy of Allergy, Asthma and Immunology on the use of IVIg in human disease.72 This consensus gave a factual review of labeled indications as licensed by the FDA and off-label indications based on (practically all) publications available. A summary of FDAapproved indications for licensed products follows:160 PID or primary humoral immunodeficiency B-cell chronic lymphocytic leukemia (hypogammaglobulinemia) HIV infection (pediatric) Kawasaki disease Idiopathic thrombocytopenia Bone marrow transplantation Off-label indications increased significantly at that point. More than 80% of the IVIg is used off-label, supported by definitely beneficial and probably beneficial indications based on category Ia-IIb evidence. From the 2006 consensus about the use of IVIg in human diseases, the main off-label uses based on category Ia-IIb evidence are summarized in Table 2.72 The concerns and risks center around adverse events (mainly the rare and serious), or around supply and economic considerations. The concern regarding the

Table 2 Off-label uses based on category Ia-IIb evidence Definitely Beneficial Graves ophthalmopathy ITP  Guillain-Barre syndrome Chronic demyelinating polyneuropathy Multifocal motor neuropathy Grade Ib Ia Ia Ia Ia Probably Beneficial Dermatomyositis and polymyositis Autoimmune uveitis Lambert-Eaton myasthenic syndrome IGM antimyelin paraprotein associated neuropathy Myasthenia gravis Stiff-man syndrome Neonatal sepsis Rotaviral enterocolitis Toxic epidermal necrolysis and Stevens Johnsons syndrome Grade IIa IIa Ib Ib Ib-IIa Ib Ia Ib IIa

These and additional IVIg products are available in Europe. Data from Orange JS, Hossny EM, Weiler CR, et al. 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. J Allergy Clin Immunol 2006;117:S52553.

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transmission of blood-borne pathogens still exists as a theoretic scenario without any practical relevance.
Dosage

Numerous publications have dealt with the question of optimal dose as replacement for patients with primary immunodeficiency disease.72,161169 After a loading dose, 400 mg/kg/mo is the generally accepted standard treatment. Diminished pulmonary function is the major cause of morbidity and mortality in patients with antibody deficiency syndrome, and it is clear that early diagnosis and prompt initiation of IVIg treatment significantly reduce these complications. Two large studies analyzed the question of dose in patients in whom IVIg treatment was started when impairment of pulmonary function was already present. In the trial by Roifman and colleagues,167 doses of 200 mg/kg/mo and 600 mg/kg/mo were compared in a cross-over study. This study and the trials conducted by Bernatowska and colleagues,170 proved that in patients on high-dose treatment, pulmonary function improved. This improvement did not take place at the lower dose level, which could be attributed to the additional anti-inflammatory effect of IVIg, which requires treatment at higher dose. The determination of whether standard doses (eg, 400 mg/kg/mo) are preferable or whether trough levels should guide IVIg treatment is still undecided. A previous study demonstrated that trough IgG levels of 500 mg/dL in patients were beneficial,52,167,171 and a recent study indicated that the rate of infection can be further reduced with a trough level of 900 mg/dL.172 This finding might be important for long-term prognosis.168 Certain conditions in patients who have PID must be treated with a higher dose. Patients with impairment of pulmonary function at presentation might need a total of 600 mg/kg/mo in one or two doses, and a few patients with chronic echo virus, meningoencephalitis, a previously fatal disease, may improve and then be maintained on 1 g/kg per dose, which has to be given repeatedly.173176 Doses of IVIg required for immunomodulation are much higher. Up to 2 g/kg are recommended and may have to be repeated.138 This usually applies to clinical situations in which IVIg is given for true immunomodulation and for the treatment of systemic inflammatory conditions (eg, Kawasaki disease).
ADVERSE EVENTS Inflammatory Reactions

Reactions during the course of, or immediately after, Ig treatment already were observed when Ig was given intramuscularly and have continued to be of concern with IVIg therapy. These reactions were anaphylactoid in nature.177183 The following list details adverse reactions to IVIg: Fever Chest tightness Chills Dyspnea Facial flush Wheezing Tachycardia Urticaria Palpitation Rash Lowering of blood pressure Anxiety

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Shock Nervousness Lumbar pain Headache Abdominal pain Nausea Vomiting Several investigators gave prophylactic steroids, antihistamines, or anti-inflammatory agents to avoid reactions or reduce severity.178,184 In many cases, adverse reactions could be avoided just by lowering the rate of infusion. The fact that patients with the most pronounced impairment of antibody production had the highest likelihood of adverse reaction made a true anaphylactic reaction most unlikely.177 The question of whether these reactions were caused by formation of immune complexes100,180,181 to anticomplementary activity or some other properties of aggregates was a subject of discussion.185,186 The fact that patients with severe adverse reactions often did not show a drop in complement levels in serum and changes in serum complement levels were not associated with adverse events indicated that other properties of Ig aggregates in addition to complement activation may be operational. IgG aggregates in IVIg products may trigger the release of pharmacologically active mediators by ligation of Fc receptors from macrophages and leucocytes.187189 Substances such as prostaglandins, platelet-activating factor, and cytokines (eg, tumor necrosis factor-a, interleukin-6) have been described to cause reactions such as fever, bronchospasm, and changes in blood pressure, which are characteristic adverse events of IVIg treatment. Another possibility for the release of mediators is that in patients with infections, the antibodies infused react with circulating microbial antigens to form immune complexes, which again trigger the release of the respective mediators. Vasoactive contaminants (eg, enzymes such as prekallikrein activator) that were present in earlier products could have contributed to reactions through the generation of bradykinin.190,191 The question of whether the frequency and severity of anaphylactoid reactions could be related to some extent to individual products, their mode of production, and their preparation is still pending. To give definite answers, controlled trials specifically designed for comparison of different products are needed, because results of such trials are scarce.172 Because IVIg was infused in large quantities, it was essential that it be free of isoagglutinins and nonagglutinating antibodies against red cells. Hemolytic reactions have been described in rare instances.
Transmission of Infectious Agents

Fortunately, because of HIV partitioning during plasma fractionation, Ig products did not transmit HIV at any time, even in the early 1980s, when the infectious agent was as yet unknown and testing for antibodies or the virus was not possible. Hepatitis C virus transmission did occur, however, with different IVIg products in the late 1980s to mid-1990s.192 In most of the products involved, ion exchange chromatography was used in purification, but one of the products was prepared by the pH4 pepsin treatment.193 Soon after cases of viral contamination were reported, additional steps and controls in the course of IVIg manufacturing were implemented. The industry responded with donor screening, donor testing, inventory management, plasma pooling, and testing. Quality control measures of viral partitioning during fractionation were introduced, and

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additional viral inactivation steps were performed. Licensed products currently are considered safe with respect to transmission of viral agents, especially HIV and hepatitis viruses.194 Unknown agents are only of theoretic risk.
Thromboembolic Events

With broad application of IVIg, especially high-dose therapy, previously rare complications have been observed and described more frequently.195 Most of the patients in whom thromboembolic events occurred in the course of mainly high-dose IVIg treatment were patients with neurologic diseases or polymorbid patients. Numerous medical conditions have been recognized as risk factors (eg, hypertension, cardiovascular disease, diabetes, kidney disease).196198 Thromboembolic complications also were observed in a few patients with primary immunodeficiency who had been treated with a regular dose. Because antibody deficiency syndromes have moved from the pediatric to the adult population and treatment with IVIg of elderly patients who have PID is not a rarity anymore, underlying morbidity (pulmonary, cardiac, renal) must be taken into consideration in IVIg treatment of patients who have PID. The mechanisms of action for thromboembolic complications are not well understood. Dalakas suggested that increased serum viscosity plays a crucial role.197 Antiphospholipid antibodies in IVIg also were mentioned as of possible importance. Wolberg and colleagues detected coagulation factor XI as a contaminant in IVIg products and showed that IVIg samples that contained factor XI shortened clotting time in factor XIdeficient plasma.183,199 Rapid infusions, which have been suggested because of the inconvenience of the regular lengthy infusion time for patients who had to receive large amounts of IVIg, seemed to be more prone to causing thromboembolic complications. The rate of adverse events after rapid infusion was higher than reported in usual standard rates of application. Some reports still favor rapid infusion, mainly because of lower cost.200,201
Renal Complications

Renal complications in the course of IVIg treatment have been described since the mid-1980s. Usually, but not exclusively, they occur with high-dose treatment. These reactions, although infrequent, resulted in severe morbidity; more than one third of the patients required dialysis, and fatalities have been reported.198,202,203 The mechanisms explaining these adverse effects included sucrose or maltose in the product, because renal lesions caused by sucrose have been known since the 1940s. Risk factors were similar to those observed in thromboembolic disease, especially old age (> 60), diabetes, and prior renal disease.204,205
ADVERSE EVENTS CAUSED BY IMMUNOGLOBULIN A

Severe (transfusion) reactions have been described in patients with gastrointestinal disease who were IgA deficient. After these observations, reactions to IVIgusually anaphylactoidwere contributed to IgA206 in the product and IgA antibodies in the patient.207209 In two patients, true anaphylactic reactions were reported; they had IgE antibodies against IgA.210 During the decades of discussion about anaphylactic/ anaphylactoid reactions to IgA, cases in which IgE antibodies could be identified as the reason for the reaction have been rare. Most patients with anaphylactoid reactions to IVIg are unable to produce antibodies of any class or specificity, and numerous patients who had IgA antibodies did not show reaction to IVIg products containing IgA.

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CURRENT STATUS AND ONGOING DEVELOPMENTS

IVIg treatment is the most commonly applied mode of Ig replacement therapy for patients with antibody deficiency syndromes and the only mode of Ig treatment for all other indications. Intravenous immunoglobulin products available in the United States can be seen in Table 3.
Home treatment with immunoglobulin for subcutaneous application

Already at the beginning of Ig treatment in the early 1950s, Janeway preferred the subcutaneous application of Ig. In 1979, Berger and colleagues described Ig replacement therapy by slow subcutaneous infusion using small, battery-operated pumps and found that the subcutaneous infusions were tolerated remarkably well with minimal local reaction and no evidence of adverse systemic effects. Later, subcutaneously applicable Ig preparations without mercury-containing preservatives were made available for clinical studies. During these trials, it became evident that Ig given subcutaneously is well tolerated.211,212 The most common side effects are local reactions lasting 12 to 24 hours after infusion. Systemic reactions seem to occur less frequently. The dose is usually 100 mg/kg/wk but might be modified slightly according to the situation of the patient. Several papers reported that this way of treatment also makes IgAdeficient individuals tolerant to IgA, so they do not show anaphylactoid reactions even if treated intravenously afterwards.208 Several licensed products for subcutaneous application are available in the United States and Europe. This mode of Ig replacement opens the way for home treatment. Some patients have a clear preference for IV therapy once or twice a month, whereas others prefer the subcutaneous way of treatment. These latter patients can choose the time at their own convenience and regard the independence gained by this procedure as a major improvement in their quality of life.
Monoclonal antibodies

In the mid-1970s, the epoch-making discovery by Jerne, Kohler, and Milstein (Nobel Prize for Medicine or Physiology, 1984) opened the way for the production of

Table 3 IVIg products currently available in the United States Manufacturer Talecris Gamunex2 Name of Product Immune globulin intravenous (human), 10% caprylate/ chromatography purified Gammagard liquid immune globulin intravenous (human) 10%(KIOVIG) Gammagard/S/D immune globulin intravenous (human) Carimune NF nanofiltered immune globulin intravenous (human) Flebogamma 5% immune globulin intravenous (human) Octagam immune globulin intravenous (human) 5% Indications PID; ITP

Baxter Baxter ZLB Behring Grifols Octapharma

PID associated with defects in humoral immunity PID, ITP, CLL, Kawasaki syndrome Immunodeficiency, ITP PID PID

Data from Sorensen R. Expert opinion regarding clinical and other outcome considerations in the formulary review of immune globulin. J Manag Care Pharm 2007;13(3):27883.

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monoclonal antibodies in virtually unlimited quantities. The hope that these antibodies would be used extensively in the prevention and treatment of infectious disease was widely expressed. Over several decades we learned that monoclonal antibodies with a single specificity recognizing a single epitope on the target antigen cannot substitute for polyclonal antibodies in prophylaxis and treatment of infectious disease. The task of humanization to arrive at products that are not recognized as antigens in the recipient became challenging. Monoclonal antibodies are widely used in the treatment of cancer and thromboembolic disease; however, their use in infectious disease is limited and they still have no place in Ig replacement therapy for antibody-deficient patients. Increasing understanding in the expression of Fc receptors, ligand binding, and signaling led to new hypotheses to explain the numerous immunomodulating properties of IVIg.213,214 Most hematopoietic cells, including phagocytes, express high-affinity Fc receptors that transduce positive signals and low affinity Fc receptors, which downmodulate cell activation to keep the balance. B cells only express the inhibitory Fc receptor. This FcR has been shown to regulate positive signals coming from the B-cell antigen receptor, which could explain the true immunosuppressive effect observed in the clinic where IVIg had a long-term effect in patients with autoimmune diseases because of autoantibodies. One is tempted to speculate that this could have been the mechanism in one of the first observations by Barandun30 while treating a patient who had antibody deficiency and hemolytic anemia. The patient turned Coombs-negative during Ig treatment. Recently, Ravetch provided experimental evidence that the suppression of inflammation is mediated by sialylation of a defined position in the Ig structure.215217 He suggested that a product containing the Fc part of the IgG with the proper sialylation might be 30-fold more effective than an IVIg product and could be produced by recombinant technology. Limited experimental evidence indicates that such a preparation could be developed into a clinical product, but history teaches that the time course of developments in this area from the first experimental evidence to successful treatment might span decades. The following list details the chronologic events leading up to the currently available treatment. 1890 Serum of rabbits immunized with tetanus toxin protected normal animals against tetanus 1901 Von Behring won the first Nobel Prize in Physiology or Medicine 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 deaths 18901910 Curative (animal sera) prepared and applied against diseases caused by toxins, bacterial disease, allergic disease and cancer 1907 Convalescent sera in the prevention of measles 19101930 Human (convalescent) sera preferred to animal sera in prevention and treatment Initiation of pepsin treatment of animal sera for reduced reactogenicity 19331938 Prevention of measles with gammaglobulin (placenta) 1940 Cold ethanol fractionation

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1949 until vaccination Prevention and treatment of poliomyelitis, measles, mumps, pertussis, and hepatitis A by Ig 1952 Treatment of PID with Ig 1960 Pepsin-treated IVIg 1970 Other chemically, enzymatically modified and unmodified (treated) IVIg products 1979 Consensus meeting on IVIg indicated for procurement of antibodies IVIg has to be safe with unimpaired function 1984  Cesar Milstein, with Georges Kohler and Niels K. Jerne, received the Nobel Prize for Physiology or Medicine for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies 1990 Consensus meeting on IVIg indicated for the provision of antibodies and immunomodulation. Interference with Fc receptor binding (targets of autoantibodies) ITP Anti-inflammatory effect: Kawasaki disease Immunosuppression  Guillain-Barre syndrome Chronic inflammatory demyelinating polyneuropathy 19952001 Consensus meeting Basically identical indications to 1990 Extensive off-label use Present FDA licensed indications Basically similar to Consensus 19952001 Numerous further indications for off-label use based on clinical studies with clear (CL1-2) evidence
SUMMARY

Soon after the first report by von Behring on toxin neutralization by serum proteins, clinical scientists took the opportunity to apply this principle to a wide range of infectious diseases. After important discoveries in the field of biochemistry, it became clear that antibodies are in the gammaglobulin fraction of serum, that serum can be fractionated to obtain gammaglobulins, and that some patients serum lacks gammaglobulins. The principle: the provision of antibodies with Ig for intramuscular use and later IVIg to prevent and treat infection, especially in patients with agammaglobulinemia (ie, antibody deficiency, PID), was the governing principle for IVIg use until the 1980s, as can be seen in the consensus of 1979. The possibility of modulation of inflammation, immunomodulation, and immunosuppression with Ig first emerged in the early 1960s and has expanded since the 1980s. The consensus of 1990 demonstrated examples of clinical use based on immunomodulation. In the last 20 years, the off-label use of Ig exploded mainly for inflammatory and hematologic, neurologic, medical, and dermatologic autoimmune diseases, often based on solid clinical

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evidence. The dose is generally 400 mg/kg/mo for the provision of antibodies, up to 2 g in single or multiple doses for immunomodulation. Concerns regarding adverse effects changed during the decades of experience. The early problems of inflammatory reactions are manageable; viral transmission has been eliminated by prompt and effective action. Serious adverse events, such as thromboembolic and renal complications, are rare; however, when they appear, especially in polymorbid patients, they are worrisome. Old and new practical developments move toward home treatment for patients who prefer this mode of therapy. The question of shortage of Ig in the course of extended use and high costs urge us to critically assess available evidence for application of this precious material in treatment. New scientific developments help us to understand the immunomodulatory function of Ig on the cellular and molecular level and may open the way for a different Ig product for immunomodulation. More than 100 years after initiation of antibody treatment and more than 50 years after treatment of patients with PID became state-of-the-art, the provision of antibodies/treatment with Ig (IV or subcutaneous) to patients who have PID remains the life-saving, classic, and first indication for IVIg, and all Ig products currently available are licensed for it.
ACKNOWLEDGMENTS

The author would like to thank Barbara Alving, MD, Department of Health and Human Services, National Institutes of Health, for providing the proceedings of the 1979 workshop and Hermann Wolf, MD, for fruitful discussions.
REFERENCES

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190. 191.

192.

in patient with X-linked agammaglobulinemia. N Engl J Med 1981;304: 127881. Mease PJ, Ochs HD, Corey L, et al. Echovirus encephalitis/myositis in X-linked agammaglobulinemia. N Engl J Med 1985;313:758. Quartier P, Foray S, Casanova JL, et al. Enteroviral meningoencephalitis in X-linked agammaglobulinemia: intensive immunoglobulin therapy and sequential viral detection in cerebrospinal fluid by polymerase chain reaction. Pediatr Infect Dis J 2000;19:11068. Part 3. Adverse reactions to immunoglobulins: methods used to produce safe immunoglobulin preparations. In: Alving BM, Finlayson JS, editors. Immunoglobulins: characteristics and uses of intravenous preparations. Proceedings of a workshop, DHHS Publication no. (FDA)-80-9005. Washington DC: US Department of Health and Human Services; 1979. p. 137225. Pirofsky B. Intravenous immune globulin therapy in hypogammaglobulinemia: a review. Am J Med 1984;76(Suppl 3a):5360. Gislason D, Hanson LA, Kjellman H, et al. Intravenous gamma-globulin infusions in patients with hypogammaglobulinemia. Vox Sang 1978;34:1438. Cunningham-Rundles C, Day NK, Wahn V, et al. Reactions to intravenous gammaglobulin infusions and immune complex formation. In: Nydegger UE, editor. Immunochemotherapy: a guide to immunoglobulin prophylaxis and therapy. London, New York: Academic Press; 1981. p. 44750. Barandun S, Morell A. Adverse reactions to immunoglobulin preparations. In: Nydegger UE, editor. Immunochemotherapy: a guide to immunoglobulin prophylaxis and therapy. London, New York: Academic Press; 1981. p. 2237. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfus Med Rev 2003;17:24151. Wolberg AS, Kon RH, Monroe DM, et al. Coagulation factor XI is a contaminant on intravenous immunoglobulin preparations. Am J Hematol 2000;65(1):304. Lederman HM, Roifman CM, Lavi S. Corticosteroids for prevention of adverse reactions to intravenous immune serum globulin infusions in hypogammaglobulinemic patients. Am J Med 1986;81:4436. Aronson DL, Finlayson JS. Historical and future therapeutic plasma derivatives (epilogue). Semin Thromb Hemost 1980;VI:12139. Eibl M. Treatment of defects of humoral immunity. In: Wedgwood RJ, Rosen FS, Paul NW, editors, Primary immunodeficiency diseases. Birth defects. New York: Alan R. Liss; 1983. p. 193200. Goodwin JS, Webb DR. Regulation of the immune response by prostaglandins. Clin Immunol Immunopathol 1980;15:10622. Passwell JH, Dayer JM, Merler E. Increased prostaglandin production by human monocytes after membrane receptor activation. J Immunol 1979;123:11520. Camussi G, Aglietta M, Coda R, et al. Release of platelet activating factor (PAF) and histamine. II. The cellular origin of human PAF: monocytes, polymorphonuclear neutrophila and basophils. Immunol 1981;42:1919. Eibl MM. PKA contamination of immunoglobulin G. [letter]. N Engl J Med 1985; 313:581. Alving BM, Hojima Y, Pisano JJ, et al. Hypotension associated with prekallikrein activator (Hageman-factor fragments) in plasma protein fraction. N Engl J Med 1978;299(2):6670. Rosenfeld EA, Shulman ST, Corydon KE, et al. Comparative safety and efficacy of two immune globulin products in Kawasaki disease. J Pediatr 1995;126:10003.

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193. Schiff RI. Transmission of viral infections through intravenous immune globulin. N Engl J Med 1994;331:164950. 194. Eibl MM. Intravenous immunoglobulins in neurological disorders: safety issues. Neurol Sci 2003;24:S2226. 195. Miller JLC, Petteway SR Jr, Lee DC. Ensuring the pathogen safety of intravenous immunoglobulin and other human plasma-derived therapeutic proteins. J Allergy Clin Immunol 2001;108(4):914.  196. Klaesson S, Ringden O, Ljungman P, et al. Does high-dose intravenous immune globulin treatment after bone marrow transplantation increase mortality in venoocclusive disease of the liver? Transplantation 1995;60(11):122530. 197. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44(2):2236. 198. Grillo JA, Gorson KC, Ropper AH, et al. Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology 2001;57: 1699701. 199. Stangel M, Muller M, Marx P. Adverse events during treatment with high-dose intravenous immunoglobulins for neurological disorders. Eur Neurol 1998;40: 1734. 200. Alving BM, Tankersley DL, Mason BL, et al. Contact-activated factors: contaminants of immunoglobulins preparations with coagulant and vasoactive properties. J Lab Clin Med 1980;96(2):33446. 201. Orbach H, Katz U, Sherer Y, et al. Intravenous immunoglobulins: adverse effects and safe administration. Clin Rev Allergy Immunol 2005;29(3):17384. 202. Kallenberg CG. A 10% ready-to-use intravenous human immunoglobulin offers potential economic advantages over a lyophilized product in the treatment of primary immunodeficiency. Clin Exp Immunol 2007;150(3):43741. 203. Brannagan TH III, Nagle KJ, Lange DJ, et al. Complications of intravenous immune globulin treatment in neurologic disease. Neurology 1996;47:6747. 204. Gaines A, Varricchio F, Kapit R, et al. Renal insufficiency and failure associated with globulin intravenous therapy. MMWR Morb Mortal Weekly Rep 1999;48: 51821. 205. Stewart RR, Winney RJ, Cash JD. Renal toxicity of intravenous immunoglobulin. Vox Sang 1993;65(3):244. 206. Orbach H, Tishler M, Shoenfeld Y. Intravenous immunoglobulin and the kidney: a two-edged sword. Semin Arthritis Rheum 2004;34(3):593601. 207. Cunningham-Rundles C, Zhou Z, Mankaroius S, et al. Long-term use of IgAdepleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies. J Clin Immunol 1993;13(4):2728. 208. Salama A, Schwind P, Schonhage K, et al. Rapid detection of antibodies to immunoglobulin A molecules by using the particle gel immunoassay. Vox Sang 2002;81(1):845. 209. Horn J, Thon V, Bartonkova D, et al. Anti-IgA antibodies in common variable immunodeficieny (CVID): diagnostic workup and therapeutic strategy. Clin Immunol 2007;122:15662. 210. Salama A, Temmesfeld B, Hippenstiel S, et al. A new strategy for the prevention of IgA anaphylactic transfusion reactions. Transfusion 2004;44(4):50911. 211. Burks AW, Sampson HA, Buckley RH. Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia: detection of IgE antibodies to IgA. N Engl J Med 1986;314(9):5604.

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212. Chapel HM, Spickett GP, Ericson D, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 2000;20(2):94100. 213. Wade N. Hybridomas: the making of a revolution. Science 1982;215(4536): 10735. 214. Baudino L, Nimmerjahn F, Azeredo da Silveira S, et al. Differential contribution of three activation IgG Fc receptors (FcgammaRI, FcgammaRIII, and FcgammaRIV) to IgG2a- and IgG2B-induced autoimmune hemolytic anemia in mice. J Immunol 2008;180(3):194853. 215. Nimmerjahn F, Ravetch JV. Fc-receptors as regulators of immunity. Adv Immunol 2007;96:179204. 216. Anthony RM, Nimmerjahn F, Ashline DJ, et al. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 2008;320(5874):3736. 217. Nimmerjahn F, Ravetch JV. The antiinflammatory activity of IgG: the intravenous IgG paradox. J Exp Med 2007;204(1):115.

I ntravenous I mmuno globulins : Evolution of Commerc ial IVIG Preparations

John A. Hooper, PhD
KEYWORDS  Intravenous immunoglobulin  Primary immunodeficiency  Manufacture  Commercial

Human immunoglobulin G (IgG) has been used to treat people with inherited immunoglobulin deficiencies since 1952 when Bruton1 infused a child with undetectable gamma globulin levels and who suffered from recurrent pneumococcal infections. Subcutaneous infusions of 3.2 g/mo produced measurable gamma globulin levels and completely eliminated pneumococcal infections. Human IgG soon became the standard treatment for patients with primary antibody deficiencies who develop chronic bacterial infections. The first human IgG produced on a large scale was known as immune serum globulin or ISG. It was produced by a cold ethanol precipitation process developed in the early 1940s by E. J. Cohn and his coworkers2,3 in the Department of Physical Chemistry at Harvard Medical School. ISG was formulated at a protein concentration of 165 mg/mL that contained 0.3 Molar glycine, 0.9% (weight/volume) sodium chloride and 0.1 g/L merthiolate. ISG solutions were adjusted to pH 6.8 0.4 and stored at 5 C. With time, ISG solutions tended to form particles (aggregates) during storage. Aggregates were generally believed to be the cause of adverse events when ISG was injected intravenously. Therefore, the first commercial immunoglobulins were restricted to intramuscular or subcutaneous injections.

INTRAVENOUS IMMUNOGLOBULIN

In 1962, spontaneous complement activation (anticomplement activity) by IgG aggregates was proposed as the principal cause of adverse side reactions when ISG was injected intravenously.4 The desire to eliminate anticomplement activity

BioCatalyst Research LLC, 217 Camelot Drive, Liberty, MO 64068, USA E-mail address: johnhooper@kc.rr.com Immunol Allergy Clin N Am 28 (2008) 765778 doi:10.1016/j.iac.2008.06.002 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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had a significant impact on intravenous immunoglobulin (IVIG) development.5,6 Some manufacturers reduced anticomplement activity by enzymatic digestion or chemical modification. The first IVIG was produced by pepsin digestion and contained a principal fragment with two antigen binding sites linked by disulfide bonds.7 The desire to reduce anticomplement activity and produce IVIGs with intact IgG as the principal component led some manufacturers to limit pepsin treatments,4 to use the more specific enzyme plasmin,8 and to chemically modify the product. Chemically modified IVIGs were produced that were structurally intact, were low in anticomplement activity, and contained no IgG fragments.911 Treatments of immunoglobulins with enzymes and chemical modification to suppress spontaneous complement activation had several unintended consequences. The treatments also reduced important antibody biological activities required for clinical efficacy. For example complement activation by antigen-antibody complexes plays an important role in the killing of encapsulated bacteria by leukocytes.12 Antibodies that are chemically and physically altered are rapidly removed from the circulatory system by the reticuloendothelial system. Thus some antibodies in enzyme-digested and chemically modified IVIGs were shown to have reduced bacterial opsonizing activities1215 and shortened circulating half-lives.1618

SECOND GENERATION INTRAVENOUS IMMUNOGLOBULIN

All commercial IVIGs are produced from large pools of human plasma by first concentrating the IgG by cold ethanol fractionation. Although IgG produced by cold ethanol fractionation is relatively pure, it contains trace amounts of highly active contaminants that have the potential to cause most of the adverse events previously attributed to aggregates. These contaminants include prekallikrein activator (which initiates production of the potent vasodilator bradykinin), prekallikrein, activated coagulation factors, complement proteins, and immunoglobulins A and M.6 Other contaminants such as plasmin and plasminogen can degrade IgG to form split products and to reduce some antibody activities during ISG storage.19 The desire to produce IVIG that contain native IgG with antibodies that are fully active led to development of IVIG using purification with anion exchange (DEAE) chromatography. The first purified IVIG contained none of the trace contaminants associated with adverse events. Some antibody biological activities such as bacterial opsonization and virus neutralization were higher than in treated products.6 Now virtually all commercial IVIGs are produced with an anion exchange chromatography step and contain relatively low levels of trace contaminants. Historically, IVIGs were freeze-dried to obtain a preparation that would be stable for 2 to 3 years. In 1986, McCue and coworkers20 reported that adjusting the pH to 4.25 produced a clear, physically stable IgG solution. Clinical studies demonstrated that patients tolerated IgG solutions formulated at a pH significantly lower than the customary range of 6.4 to 7.2.21 This product represented a major advance in IVIG product formulation. Table 1 lists commercial IVIG preparations currently (or soon to be) available in North America. Of the nine products licensed in the United States, seven are produced by cold ethanol fractionation followed by purification using ion exchange chromatography. Seven products are formulated as liquids and two are freeze-dried. All are produced with specific virus inactivation or removal steps incorporated into their manufacturing procedures.

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DEVELOPMENT OF VIRUS ELIMINATION PROCEDURES

Transmission of homologous serum hepatitis through whole blood, plasma, and serum was a great concern during development of human plasma proteins.1 Yellow fever vaccines stabilized with human serum had produced 23,000 cases of hepatitis in military personnel. Pooled human plasma presented a higher risk of hepatitis transmission than whole blood because of the increased probability that pooled plasma would be contaminated by one or more donors. Human albumin solutions were also responsible for hepatitis transmission.22 Heat can be used to inactivate viruses and proteins. The destruction temperature of a protein is sharply defined and is different for each protein.23 In the presence of substrate, enzymes can be heated to temperatures 10 degrees higher than in the absence of substrate.23 In 1948, Gellis and coworkers22 reported that hepatitis transmission by albumin was eliminated by heating it for 10 hours at 60 C. Virus inactivation of albumin by heat treatment was possible because of the discovery that addition of stabilizers increased the heat resistance of albumin. Human albumin has many binding sites for hydrophobic molecules and plays a major role in the transport of fatty acids. Filling these sites with the stabilizers acetyltryptophan and caprylic acid allows albumin to withstand heating for 10 hours at 60 C. Since albumin has no measurable biological activity, the full impact of heating albumin is not known. Unfortunately, other plasma proteins in solution are inactivated by heat and early attempts to inactivate viruses in high risk plasma products were unsuccessful. High risk plasma products included fibrinogen, Factor VIII concentrate, and Factor IX.24 Heated albumin solutions and immunoglobulins produced by cold ethanol fractionation were considered to be low-risk products.24 Factor VIII is rapidly inactivated when heated in solution. However, dried Factor VIII is relatively heat stable under certain conditions. This observation led to development of heat-treated Factor VIII preparations in the 1980s.25,26 Fortunately, HIV was also inactivated in heated Factor VIII but the products had lower biological activities, were relatively insoluble, and produced a higher incidence of Factor VIII inhibitors. Unfortunately, non-A, non-B hepatitis was not inactivated.25 The perception that immunoglobulins produced by cold ethanol fractionation had a low risk of transmitting virus infections changed in 1983 when Lane reported that an experimental IVIG produced by cold ethanol fractionation transmitted non-A, non-B hepatitis.27 During this same period, HIV was isolated and shown to be transmitted by blood and blood products.28,29 The emergence of HIV and reports of non-A, non-B hepatitis transmission by some IVIG products30,31 caused manufacturers and regulatory agencies to examine existing IVIG manufacturing procedures for their capacity to eliminate viruses.3241 Development of dedicated virus inactivation procedures for IVIG production was also initiated.42,43
VIRUS INACTIVATION OF INTRAVENOUS IMMUNOGLOBULIN

Studies of IVIG manufacturing procedures revealed that cold ethanol fractionation removes viruses by two mechanisms: inactivation and partitioning. Several laboratories demonstrated that HIV is inactivated by cold ethanol under conditions used in IVIG production.3336,41 However, vesicular stomatitis virus and Sindbis virus, both used as models for the hepatitis C virus (HCV), formerly known as non-A, non-B, were stable under similar conditions.41 Given the success of heat treatment in producing albumin with a low-risk of transmitting hepatitis, heat treatments for IVIG were evaluated. One IVIG was stabilized with 33% (weight/weight) sorbitol at pH 5.5 and heated at 60 C for 10 hours.43 Several

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Table 1 Production and properties of commercial immunoglobulins Trade Names Gammagard S/D Manufacturer Baxter HealthCare Corp Registrations United States, Canada, European Union Manufacturing Procedure Cold ethanol fractionation, DEAE chromatography, S/D, pH 6.8 0.4, freezedried Composition Comments

<1 mg/mL IgA 50 mg/mL; 8.5 mg/mL NaCl, 0.3 M glycine, 20 mg/mL PEG, 3 mg/mL albumin, 20 mg/mL glucose

Gammagard Liquid, KIOVIG

Baxter HealthCare Corp

United States, European Union

100 mg/mL; 0.25 M Cold ethanol fractionation, DEAE glycine chromatography, S/D, nanofiltration, pH 4.85 0.25, liquid Cold ethanol fractionation, octanoic acid/calcium acetate treatment, S/D, liquid 50 mg/mL; 0.3 M glycine

Intratect

Biotest

Germany, European Union

Vigam

Bio Products Laboratory

England

50 mg/mL; IgG, 20 mg/mL human albumin, sucrose, glycine, pH 4.85.1 30. 60, 90 or 120 mg/mL; 100 mg/mL sucrose, 1.2 mg/mL NaCl 120 mg/mL; 100 mM L-isoleucine, 120 mM L-proline, 80 mM Nicotimamide

In US clinical trials (Gammaplex)

Carimune NF

CSL Behring AG

United States, European Union

Cold ethanol fractionation, pepsin treatment, nanofiltration, pH 6.6 0.2, freeze-dried Cold ethanol fractionation, pepsin treatment, DEAE Sephadex batch adsorption, nanofiltration, pH 5.3 liquid

Sandoglobulin NF liquid Carimune NF liquid

CSL Behring AG

Canada

Privigen

CSL Behring AG

United States

Cold ethanol fractionation, octanoic acid fractionation, anion exchange chromatography, nanofiltration, pH 4.8 0.2, liquid Cold ethanol, fatty alcohol, DEAE chromatography, activated carbon, heated 10 h @ 60 , pH 6.8 0.4, liquid Cold ethanol, polyethylene glycol precipitation, ion exchange chromatography, 10 h @ 60 , pH 5.5 0.5, liquid Cold ethanol, polyethylene glycol precipitation, ion exchange chromatography, pH 4 @ 37 , 10 h @ 60 , S/D, nanofiltration, pH 5.5 0.5, liquid

100 mg/mL; 0.25 M proline

Vivaglobin

CSL Behring AG

United States

160 mg/mL; 3 g/L NaCl, 0.25 N glycine

Formulated for subcutaneous injection

Flebogamma 5%

Instituto Grifols, SA United States, Spain

50 mg/mL; 50 mg/mL D-sorbitol, <6 mg/mL polyethylene glycol

Flebogamma 5% DIF

Instituto Grifols, SA United States

50 mg/mL; 50 mg/mL D-sorbitol, <3 mg/mL polyethylene glycol

4 virus elimination steps

Intravenous Immunoglobulins

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Table 1 (continued) Trade Names Octagam Manufacturer Octapharma Pharmazeutika Produktionsges.m.b.H. Omrix Biopharmaceuticals Ltd Registrations United States, European Union Manufacturing Procedure Cold ethanol fractionation, S/D, 24 h @ pH 4, pH 5.5 0.4, liquid Cold ethanol fractionation, S/D, 24 h @ pH 4, pH 5.5 0.4, liquid Cold ethanol fractionation, caprylate precipitation, Q Sepharose-ANX Sepharose chromatography, pH 4.25 0.25, liquid Composition 50 mg/mL; 100 mg/mL maltose Comments

Omr-IgG-am

Israel

50 mg/mL; 100 mg/mL maltose

In US clinical trials

Gamunex

Talecris Biotherapeutics, Inc

United States European Union

100 mg/mL; 0.2 M glycine

Abbreviations: IgA, immunoglobulin A; NF, nanofiltration; PEG, polyethylene glycol; S/D, solvent-detergent.

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enveloped viruses and one nonenveloped virus were studied. All viruses were completely inactivated except for HCV. No substantial changes in IgG physicochemical and biological properties were reported. In 1988, Horowitz42 reported that a solvent-detergent process, originally developed to inactivate viruses in Factor VIII concentrates, was an effective virus inactivation process for IgG solutions. Solvent-detergent virus inactivation was rapidly adopted by several IVIG manufacturers (Table 2). Inactivation of hepatitis C and bovine viral diarrhea virus (BVDV, a surrogate for HCV) was reported in liquid IVIG formulated at pH 4.25 and incubated for 21 days at 21 .38 Pepsin digestion at pH 4 and 37 has also been shown to inactivate several enveloped viruses.39,40 Recently, incubation of immunoglobulin solutions with caprylic acid has been shown to be an effective procedure for inactivating enveloped viruses.44
VIRUS REMOVAL (NANOFILTRATION)

Manufacturers have long known that clarification filtration of cold ethanol fractionation intermediates in the presence of a filter aid is an effective virus removal procedure. Some manufacturers have validated such processes as virus removal steps (see Table 2). In 1994, Burnouf-Radosevich and colleagues45 reported virus removal from Factor IX and Factor XI solutions by newly developed hollow fiber nanofiltration filters. The filters were composed of cellulose layers treated to produce mean pore sizes of 15 2 and 35 2 nanometers (nm). Virus spiking experiments demonstrated that a single dead-end filtration with the 35 nm filter removed >5.7 to 7.8 log10 of HIV-1, BVDV, porcine pseudorabies virus (PRV) reovirus type 3, simian virus 40 (SV 40), and bovine parvovirus, a small (1825 nm) nonenveloped virus.45

Table 2 Dedicated virus inactivation and removal procedures used in IVIG production Virus Inactivation/Removal Procedure Solvent-detergent inactivation Product Gammagard S/D Gammagard Liquid Flebogamma 5% DIF Octagam Omr-IgG-am Heat inactivation (10 h at 60 C) Vivaglobin Flebogamma 5% Flebogamma 5% DIF Removal by nanofiltration Gammagard Liquid Carimune NF Privigen pH 4 incubation (in process) Flebogamma 5% DIF Octagam Omr-IgG-am Privigen Low pH incubation in final container (21 d) Low pH incubation at elevated temp in final container Pepsin treatment Caprylic acid virus inactivation Gamunex Gammagard Liquid Carimune NF Gamunex

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In studies of immunoglobulin solutions with protein concentrations up to 12 mg/mL, OGrady and colleagues46 demonstrated that the 35 nm filter removed 67 log10 mouse type C retrovirus, SV 40 and PRV, whereas poliovirus was removed by only a 15 nm filter. Similar results were obtained with 70 mg/mL IgG solutions.47 Omar and Kempf48 studied the effectiveness of nanofiltration to remove small nonenveloped viruses. The viruses studied were bovine enterovirus (BEV,w30 nm), bovine parvovirus (BPV,w1825 nm) and minute virus of mice (MVM,w1825 nm). Nanofiltration was performed with filters having nominal pore sizes of 20 and 50 nm. Despite their small size, each virus was efficiently removed from 10 mg/mL IgG solutions. The authors demonstrated that removal of viruses smaller in diameter than the pore sizes of the nanofilter was due to antibodies bound to the viruses.48 Nanofiltration has been adopted by several IVIG manufacturers (see Table 2).
DONOR SCREENING AND PLASMA TESTING

Concomitant with development of virus inactivation and removal procedures, scientists also recognized the importance of eliminating infected donors and developed more sensitive tests for blood-borne pathogens. Although people with illnesses are always excluded from donating blood or plasma, some donors do not feel sick or have clinical symptoms in the early stages of an infection. During this time (window period), blood or plasma donations may transmit an infection. Thus development of donor screening tests involved not only tests for new pathogens but also tests of ever increasing sensitivity to eliminate window period infections. Gurtler49 has reviewed blood-borne pathogens with respect to their relevance to transfusion. Relevant pathogens are considered to be human pathogens that cause chronic, progressive wasting, or lethal diseases; and some infectious agents that are not prevalent in the transfused population. By these criteria, hepatitis B virus (HBV), HCV, and human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2) were characterized as relevant. Parvovirus B19, cytomegalovirus, and hepatitis A viruses (HAV) were classified as occasionally relevant. Since this review was published, nonenveloped viruses such as Parvovirus B19 and HAV have become more relevant and the Severe Acute Respiratory Syndrome-Corona virus (SARS-CoV) and West Nile virus (WNV) have emerged. Thus relevance of pathogens to transfusion is an evolving concept. Given the early concern about hepatitis transmission, identification of hepatitis viruses and development of sensitive donor screening tests became a high priority. A sensitive test for HBV was developed in 197250 and was used to eliminate infected donors. Unfortunately, the HBV test did not eliminate transfusion-related hepatitis and the search for one or more non-A, non-B hepatitis viruses was initiated. The AIDS epidemic led to rapid development of a screening test for antibodies to human immunodeficiency virus (HIV-1) in 1984.51 In 1989 the genome of a non-A, non-B hepatitis virus was isolated and used to develop a donor screening test for HCV.52 Today, plasma is screened for antibodies to syphilis, HIV-1, HIV-2, and HCV, and for HBV and HIV antigens. Extremely sensitive tests for HCV, HIV-1, HBV, and parvovirus B19 nucleic acids have recently been introduced and are now being used to further eliminate window period donations.
PRION REMOVAL

The risk of transmitting prion diseases such as Creutztfedt-Jakob disease (CJD) or Variant Creutzfeldt-Jakob disease (vCJD) by transfusions of human blood or blood products is theoretical at this time. However, the incubation time for development of CJD disease is so long that it is difficult to quantify the risk.

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There is enough uncertainty about the relationship of vCJD to bovine spongiform encephalopathy (BSE) that regulatory agencies have take steps to reduce the risk. Donors that have spent R6 months in the United Kingdom from 1986 to the present are not permitted to donate blood or plasma in the United States and Europe. The recent observation that BSE and scrapie are transmitted from sheep to sheep by transfusions may support this donor deferral program. Trejo and colleagues53 studied removal of hamster scrapie protein (PrPsc) during two steps in IVIG production. Western Blot and infectivity tests demonstrated that PrPsc was removed during two filtration steps. One of the steps was a depth filtration step that is common to all IVIG manufacturing procedures. A similar study was performed by Gregori and colleagues.54 Proteinase K resistant PrP (PrPres) was determined by Western Blot analysis whereas infectivity was measured in hamsters. The authors observed that depth filtration in the presence of filter aids and nanofiltration removed PrPres reactivity and transmissable spongiform encephalopathy (TSE) infectivity.
CLINICAL TRIALS IN PRIMARY IMMUNODEFICIENCY

In the United States, clinical trials in subjects with primary immunodeficiency have become increasingly standardized.55 The Food and Drug Administration (FDA) recommends that studies measure the rate of serious bacterial infections during regular infusions of investigational IVIG for 12 months to avoid seasonal biases. Serious infections are defined as bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess. Diagnostic criteria are listed. Statistical analysis should demonstrate that the upper 99% one-sided confidence interval for the frequency of acute serious bacterial infections is less than one per subject per year.55 Infusional adverse events are now defined as those that occur up to 72 hours following an infusion of test product, regardless of other factors that may impact a possible causal association with product administration. The target for this safety endpoint is an upper 95% one-sided confidence limit of less than 0.40.55 Pharmacokinetic (PK) data are to be obtained from at least 20 patients. The analysis should include total IgG and several specific antibodies to derive a plasma concentration-time curve, half-life, area under the curve (AUC0-t; AUC0-infinity), volume of distribution, maximum concentration (Cmax), time from start of infusion to Cmax (Tmax), and elimination rate constants. Serum samples for these antibody measurements should be taken after a washout period of 3 to 5 estimated half-lives (35 infusions) investigational IGIV. The FDA also desires that trough IgG and IgG subclass levels be measured monthly.55 The results of these policies are illustrated in Table 3. The time period for recording infusional or temporally associated adverse events has been extended from 30 minutes to 72 hours postinfusion. Each study has reported the incidence of acute serious bacterial infections and other bacterial infections. Although not shown in Table 3, pharmacokinetic studies were also performed for each product. The number of PK subjects ranged from 1462 to 5757.
TRENDS IN IVIG MANUFACTURING

As shown in Table 1, most IVIG products are still produced by cold ethanol fractionation but are now further purified with anion exchange chromatography (DEAE anion exchangers or an equivalent). Plasma fractionation by cold ethanol fractionation involves precipitating proteins by adjusting pH, salt concentration, temperature, and ethanol concentration. Precipitated proteins are removed from proteins still in solution

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Table 3 Recent clinical trials in patients with primary immunodeficiency disorders Study Duration (Months) 6 12 12 12 9 12 12 15 Patients Treated 42 51 46 61 73 46 80 51 Acute Serious Bacterial Infect /subj/y 0 0.061 0.021 0 0.07 0.1 0.08 0.04 Other Bacterial Infect /subj/y 3.65 NR 1.96 0.07 0.18 0 3.55 4.4 Related, Temporally Associated AEs (% of Infusions) 21.7%a 8.2%c 11.8%c 31.2%c 5.7%a 5.5%b 18.5%b Local, 49%; systemic, 5.4%

Product Carimune NF Liquid (12%) Flebogamma 5% Flebogamma 5% DIF Gammagard liquid 10% Gamunex 10% Octagam 5% Privigen 10% Vivaglobin 16%

Dose 200800 mg/Kg/2128 d 300600 mg/Kg/2128 d 300600 mg/Kg/2128 d 300600 mg/Kg/2128 d 100600 mg/Kg/2128 d 300600 mg/Kg/2128 d 200888 mg/Kg/2128 d 34352 mg/Kg/wk

Drug-Related SAEs 0 2 0 2 (1 patient) 0 0 5 (1 subject) 0

Abbreviations: AE, adverse event; infect/subj/y, infections per subject per year NF, nanofiltration; SAE, serious adverse event. a 048 h postinfusion. b 030 min postinfusion. c 072 h postinfusion. Data from Refs.5363

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Table 4 United States IVIG distribution data Year 1998 2002 2003 2004 2005 2006 2007
a

Kg 15,000 23,000 24,900 26,900 28,200 32,400 34,200

% Increase 53% 8% 8% 5% 15% 6%

Liters of Plasmaa 4,285,714 6,571,429 7,114,286 7,685,714 8,057,143 9,257,143 9,771,429

Assumes 3.5 g IgG obtained per liter of plasma.

by filtration or centrifugation. The most abundant plasma proteins, IgG and albumin, have vastly different physicochemical properties and are readily separated. However, some IgG and albumin is distributed to other fractions at each precipitation step. In the classical Cohn-Oncley process, fraction II (IgG) was further purified by at least three additional precipitations with IgG losses at each step. Since IgG production is the driving force behind plasma manufacturing capacity, manufacturers have turned their attention to increasing the amount of purified IgG from plasma. Some manufacturers limit IgG precipitation from plasma to a single cold ethanol precipitation step to produce what Cohn referred to as fraction I1II1III. IgG losses are minimized by using I1II1III (or II1III if fraction I-fibrinogen is precipitated earlier) as the starting material for anion exchange chromatography and the virus inactivation and removal steps that have been incorporated into the process. The importance of increasing IgG yield is illustrated in Table 4. Demand for IVIG has increased 128% in the past decade. Manufacturers have been able to meet demand by acquiring underutilized facilities, expanding existing facilities, building new facilities, and increasing yield. IVIG manufacturing changes have been accompanied by an increase in clinical trials in patients with primary immunodeficiency. There is also a trend to formulate IVIGs as solutions with a protein concentration of 100 mg/mL (10% solutions) and a low pH that favors product stability (pH 4.3 to 5.0.) The increase in IgG concentration from 5% to 10% reduces infusion time, an important feature for patients with primary immunodeficiency who receive large doses every 21 to 28 days all their life. Ten percent IVIGs at low pH are more stable at low ionic strength and therefore sodium chloride is no longer added. In addition, carbohydrate stabilizers are no longer required. Because their tendency to precipitate at increased ionic strength, products of this type may not be diluted with saline or mixed with other IVIGs that contain sodium chloride.5658
REFERENCES

1. Bruton OC. Agammaglobulinema. Pediatrics 1952;9:7227. 2. Cohn EJ, Strong LE, Hughes WL Jr, et al. Preparation and properties of serum and plasma proteins III: a system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 1946; 68:45975. 3. Oncley JL, Melin M, Richert DA, et al. The separation of the antibodies, isoagglutinins, prothrombin, plasminogen and beta-lipoprotein into subfractions of human plasma. J Am Chem Soc 1949;71:54150.

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4. Barandun S, Kistler P, Jeunet F, et al. Intravenous administration of human gamma globulin. Vox Sang 1962;7:15774. 5. Aronson DL, Finlayson JS. Historical and future therapeutic plasma derivatives (Epilogue). Semin Thromb Hemost 1980;VI:12319. 6. Hooper JA, Alpern M, Mankarious S. Immunoglobulin manufacturing procedures. In: Krijnen HW, Strengers PFW, van Aken WG, editors. Immunoglobulins. Amsterdam: Central Laboratory of the Netherlands Red Cross Blood Transfusion Service; 1988. p. 36180. 7. Schultze HE, Schwick G. Uber neue Moglichkeiten intravenoser gammaglobulinapplikation. Dtsch Med Wochenschr 1962;87:164350. 8. Sgouris JT. The preparation of plasmin-treated immune serum globulin for intravenous application. Vox Sang 1967;13:7184. 9. Stephan W. Undegraded human immunoglobulin for intravenous use. Vox Sang 1975;28:42237. 10. Masuho Y, Tomibe K, Matsuzawa K, et al. Development of an intravenous gamma-globulin with Fc activities I: preparation and characteristics of S-sulfonated human gamma-globulin. Vox Sang 1977;32:17581. 11. Schroeder DD, Tankersley DL, Lundblad JL. A new preparation of modified immune serum globulin (human) suitable for intravenous administration I: standardization of the reduction and alkylation reaction. Vox Sang 1980;40:37382. 12. Pollack M. Antibody activity against Pseudomonas aeruginosa in immune globulins prepared for intravenous use in humans. J Infect Dis 1983;147:10908. 13. Kim KS, Wass CA, Kang JH, et al. Functional activities of various preparations of human intravenous immunoglobulin against type III group B streptococcus. J Infect Dis 1986;153:10927. 14. Bender S, Hetherington S. Haemophilus influenzae type b opsonins of intravenous imunoglobulins. J Clin Immunol 1987;7:47580. 15. Steele RW, Steele RW. Functional capacity of immunoglobulin G preparations and the F(ab0 )2 split product. J Clin Microbiol 1989;27:64064. 16. Janeway CA, Merler E, Rosen FS, et al. Intravenous gamma globulin. Metabolism of gamma globulin fragments in normal and agammaglobulinemic persons. N Engl J Med 1968;278:91923. 17. Winston DJ, Ho WG, Rasmussen LE, et al. Use of intravenous immune globulin in patients receiving bone marrow transplants. J Clin Immunol 1982;2(April Supplement):42S7S. 18. Hagenbeek A, Brummelhuis GJ, Donkers A, et al. Rapid clearance of cytomegalovirus-specific IgG after repeated intravenous infusions of human immunoglobulin into allogeneic bone marrow transplant recipients. J Infect Dis 1987;155: 897902. 19. Tankersley DL, Alving BM, Yi M, et al. Predictive tests for fragmentation of immune globulins. In: Alving BM, Finlayson JS, editors. Immunoglobulins, characteristics and uses of intravenous preparations. Washington, DC: US Government Printing Office; 1980. p. 1737. 20. McCue JP, Hein RH, Tenold R. Three generations of immunoglobulin G preparations for clinical use. Rev Infect Dis 1986;8(Supplement):S37481. 21. Schiff RI. Intravenous gammaglobulin: pharmacology, clinical uses and mechanisms of action. Pediatr Allergy Immunol 1994;5:6387. 22. Gellis SS, Neefe JR, Stokes J, et al. Chemical, clinical and immunological studies on the products of human plasma fractionation. XXXVI. Inactivation of the virus of homologous serum hepatitis in the solutions of normal human serum by means of heat. J Clin Invest 1948;27:23944.

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23. Dixon M, Webb EC. Enzyme isolation: methods of purification. In: Dixon M, Webb EC, editors. Enzymes. New York: Academic Press; 1964. p. 367. 24. Gerety RJ, Aronson DL. Plasma derivatives and viral hepatitis. Transfusion 1982; 22:34751. 25. Hollinger FB, Dolana G, Thomas W, et al. Reduction in risk of hepatitis transmission by heat treatment of a human Factor VIII concentrate. J Infect Dis 1984;150:25062. 26. Colvin BT, Rizza CR, Hill FGH, et al. Effect of dry-heating of coagulation factor concentrates at 180 C for 72 hours on transmission of non-A, non-B hepatitis. Lancet 1988;ii:8146. 27. Lane RS. Non-A, non-B hepatitis from intravenous immunoglobulin. Lancet 1983; i:9745.  28. Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for AIDS. Science 1983;220:86871. 29. Centers for Disease Control. Provisional public health service interagency recommendations for screening donated blood and plasma for antibody to the virus causing acquired immunodeficiency syndrome. MMWR Morb Mortal Wkly Rep 1985;34:15. 30. Ochs HD, Fisher SG, Virant FS, et al. Non-A, non-B hepatitis after intravenous gammaglobulin. Lancet 1985;i:3223. 31. Bjorkander J, Cunningham-Rundles C, Lundin P, et al. Intravenous immunoglobulin prophylaxis causing liver damage in 16 of 77 patients with hypogammglobulinemia or IgG subclass deficiency. Am J Med 1988;84:10711. 32. Prince AM, Stephan W, Dichtelmuller H, et al. Inactivation of the Hutchinson strain of non-A, non-B hepatitis virus by combined use of -propiolactone and ultraviolet irradiation. J Med Virol 1985;16:11925. 33. Piszkiewicz D, Kingdon H, Apfelsweig R, et al. Inactivation of HTLVIII/LAV during plasma fractionation. Lancet 1985;ii:11889. 34. Wells MA, Wittek AE, Epstein JS, et al. Inactivation and partition of human T-cell lymphotrophic virus, type III, during ethanol fractionation of plasma. Transfusion 1986;26:2103. 35. Mitra G, Wong MF, Mozen MM, et al. Elimination of infectious retroviruses during preparation of immunoglobulin. Transfusion 1986;26:3947.    36. Henin Y, Marechal V, Barre-Sinoussi F, et al. Inactivation and partition of human immunodeficiency virus during Kistler and Nitschmann fractionation of human blood plasma. Vox Sang 1988;54:7883. 37. Yei S, Yu MW, Tankersley DL. Partitioning of hepatitis C virus during Cohn-Oncley fractionation of plasma. Transfusion 1992;32:8248. 38. Louie RE, Galloway CJ, Dumas ML, et al. Inactivation of hepatitis C virus in low pH intravenous immunoglobulin. Biologicals 1994;22:139. 39. Reid KG, Cuthbertson B, Jones ADL, et al. Potential contribution of mild pepsin treatment at pH 4 to the viral safety of human immunoglobulin products. Vox Sang 1988;55:7580. 40. Kempf C, Jentsch P, Poirier B, et al. Virus inactivation during production of intravenous immunoglobulin. Transfusion 1991;31:4237. 41. Hamamoto Y, Harada S, Yamamoto N, et al. Elimination of viruses (human immunodeficiency, hepatitis B, vesicular stomatitis and sindbis viruses) from an intravenous immunoglobulin preparation. Vox Sang 1987;53:659. 42. Horowitz B. Preparation of virus sterilized immune globulin solutions by treatment with organic solvent/detergent mixtures. In: Krijnen HW, Strengers PFW, van Aken WG, editors. Immunoglobulins. Amsterdam: Central Laboratory of the Netherlands Red Cross Blood Transfusion Service; 1988. p. 28595.

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43. Funakoshi S, Uemura Y, Yamamoto N. Virus inactivation and elimination by liquid heat treatment and PEG fractionation in the manufacture of immune globulin intravenous. In: Krijnen HW, Strengers PFW, van Aken WG, editors. Immunoglobulins. Amsterdam: Central Laboratory of the Netherlands Red Cross Blood Transfusion Service; 1988. p. 31325. 44. Korneyeva M, Hotta J, Lebing W, et al. Enveloped virus inactivation by Caprylate: a robust alternative to solvent-detergent treatment in plasma derived intermediates. Biologicals 2002;30:15362. 45. Burnouf-Radosevich M, Appourchaux P, Huart J, et al. Nanofiltration, a new specific virus elimination method applied to high-purity Factor IX and Factor XI concentrates. Vox Sang 1994;67:1328. 46. OGrady J, Losikoff J, Poily A, et al. Virus removal studies using nanofiltration membranes. Dev Biol Stand 1996;88:31926. 47. Troccoli NM, McIver J, Losikoff A, et al. Removal of viruses from human intravenous immune globulin by 35 nm nanofiltration. Biologicals 1998;26:3219. 48. Omar A, Kempf C. Removal of neutralized model parvoviruses and enteroviruses in human IgG solutions by nanofiltration. Transfusion 2002;42:100510. 49. Gurtler L. Blood-borne viral infections. Blood Coagul Fibrinolysis 1994;5:S510. 50. Alter HJ, Holland PV, Purcell RH, et al. The Ausria test: critical evaluation of sensitivity and specificity. Blood 1973;42:94757. 51. Sarngadharan MG, Popovic M, Bruch L, et al. Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in serum of patients with AIDS. Science 1984;224:5068. 52. Kuo G, Choo Q-L, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989;244:3624. 53. Trejo SR, Hotta J, Lebing W, et al. Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 2003;84:17687. 54. Gregori L, Maring J, MacAuley C, et al. Partitioning of TSE infectivity during ethanol fractionation of human plasma. Biologicals 2004;32:110. 55. Guidance for Industry. Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency. Rockville (MD): U.S. Department of Health and Human Services, Food and Drug Administration. Center for Biologics Evaluation and Research; 2005. 56. Prescribing information, Gamunex, Talecris Biotherapeutics, Inc, November 2005. 57. Prescribing information, Gammagard Liquid, Baxter Healthcare Corporation, April 2005. 58. Prescribing information, Privigen, CSL Behring LLC, July 2007. 59. Prescribing information, Vivaglobin, CSL Behring LLC, April 2007. 60. Prescribing information, Flebogamma 5% DIF, Instituto Grifols. S.A. 61. Prescribing information, Octagam. Octapharma Pharmazeutika Produktionges m.b.H, March 2007. 62. Prescribing information, Carimune NF, ZLB Behring AG, January 2005. 63. Prescribing information, Gammagard S/D, Baxter Healthcare Corporation, March 2007.

Sub cut a ne ous Administration of IgG

Melvin Berger, MD, PhDa,b,c
KEYWORDS     IsG  Primary immune deficiency Subcutaneous  IgG  Efficacy Pharmacokinetics  Quality of life Adverse effects

Systemic availability of exogenous antibodies injected subcutaneously (SC) into humans was recognized more than 100 years ago, when immune animal sera were used as the major treatment of diphtheria and tetanus.1 Indeed, the characteristics of adsorption of IgG from SC sites were well understood even then: A certain time must elapse from the injection.until its healing activity in the infected parts of the body can develop. (Antibody) injected under the skin does not pass straight into blood vessels but first into the lymphatic vessels. From here it takes several hours before passing gradually into the blood stream and further time still is needed before it is diffused not only everywhere in the blood stream but also in the extra-vascular fluids.1 Despite the slower kinetics of adsorption and distribution of IgG given by the SC, as opposed to the intravenous (IV), route, SC administration of the exogenous antisera was preferred because of its freedom from the severe and often lifethreatening systemic reactions that accompanied IV injections of animal proteins. Decades later, similar freedom from systemic adverse reactions prompted the use of slow SC infusions of human IgG concentrates in patients who had primary immune deficiency diseases (PIDD) and poor tolerance of intramuscular (IM) injections or the newly developed IV preparations.26 Several studies have shown that subcutaneous immunoglobulin (SCIG) has similar efficacy to intravenous immunoglobulin (IVIG) in preventing infections in PIDD patients. The freedom from systemic adverse effects and the ease with which SC can be administered at home has led to its increasing popularity in recent years, and to documented improvement in quality of life for PIDD patients.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA Department of Pathology, Case Western Reserve University, Cleveland, OH, USA c Jeffrey Modell Center for Primary Immune Deficiencies, Division of Allergy-Immunology, Rainbow Babies and Childrens Hospital, University Hospitals of ClevelandCase Medical Center, R B & C Room 504, MS 6008B, 11100 Euclid Avenue, Cleveland, OH 44106, USA E-mail address: melvin.berger@uhhospitals.org
b

Immunol Allergy Clin N Am 28 (2008) 779802 doi:10.1016/j.iac.2008.07.002 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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EFFICACY

Although several studies suggest that SCIG treatment is comparable to IV treatment in preventing infections in PIDD patients, few direct comparisons have been made. Chapel and colleagues7 used a composite score for major and moderate infections in a crossover study comparing the two routes, and reported slight, but not significantly different, decreases in infection in patients on SC treatment. The number of days lost from work or school due to illness showed no difference in the two groups.7 This study included 24 subjects who completed 1 year of treatment on each route, but different IgG preparations were used for the different routes.7 Pac and Bernakowska8 reported a nearly 50% reduction in episodes of infection and days of antibiotics on 13 months of SC as opposed to the preceding year of IV treatment in the same patients. Gardulf and colleagues9 showed a reduction in days in hospital per year due to infection in PIDD patients on SC versus those on IV treatment, but the statistical significance of this difference was not reported. In a recent study in Germany in which patients on SCIG were asked to compare retrospectively their previous IVIG with current SCIG treatment regimens, the reported incidence of infection dropped from 2.8 2.0 days in 6 months on IV to 1.9 1.9 days in 6 months on SC (P 5 .021).10 The author and his colleagues recently completed a randomized, crossover study in the United States, in which 11 patients received the same monthly dose of a single preparation of IgG by the IV and SC routes for 6 months each. Thirteen episodes of infection occurred during the IV phase versus only 9 episodes during the SC phase.11 In one of the largest and most closely monitored studies of SCIG, which included 51 patients in the United States in a 12-month efficacy period, Ochs and colleagues12 reported 0.04 serious infections and 4.4 nonserious infections per patient per year. In a 6-month study of 47 patients on the same SC preparation in the European Union and Brazil, the annualized incidence of serious infections was also 0.04 per patient per year and the incidence of nonserious infections was 4.3 per patient per year.13 These results are comparable to the overall mean of 0.068 serious infections per patient per year and 3.02 nonserious infections per year in the licensing trials of all IVIG preparations licensed in the United States since 2000. Thus, the results indicate that SCIG is equal in efficacy to IVIG in preventing infections in PIDD patients. Although it may be postulated that elimination of periods with low IgG levels toward the end of IVIG dosing intervals (see later discussion) might result in better long-term freedom from morbidity due to chronic sinus or lung infection in PIDD patients, data are not available that would allow comparison of the long-term effects of SC versus IV IgG administration on the development of bronchiectasis or other changes on CT scans, nor on deterioration of pulmonary function in patients who have PIDD. Similarly, no data are available comparing the efficacy of SC versus IV IgG on the persistence or progression of chronic sinus disease in PIDD patients with that problem, or on other complications of PIDD.

PHARMACOKINETICS

Few published data report traditional pharmacokinetic parameters for IgG administered by the SC route in immunodeficiency patients. Studies in rabbits have shown that the peak serum IgG concentration is reached 3.2 days after SC injection of human IgG and that the bioavailability of IgG given IM or SC is less than that of IgG given IV.14 In another rabbit study, using a preparation of IgG currently marketed in the United States for IV use, more than 120% of the IV dose was necessary to achieve the same area under the curve (AUC) of IgG versus time for SC versus IV administration.15

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The Food and Drug Administration (FDA) criteria for approval of new IgG preparations for IV administration include the requirement that pharmacokinetic parameters for the new preparation be similar to historical values for previously licensed IV preparations.16 The parameters to be reported include the volume of distribution; plasma concentration time curve, including the time at which the maximum concentration is reached and the maximum concentration that is achieved; AUC; half-life; and elimination rate constants.16 Partly because of the preclinical data mentioned earlier, partly because of data received by the FDA showing that monoclonal antibodies and therapeutic Fc fusion proteins have lower bioavailability when given by the SC or IM as compared with IV route, and partly because of uncertainty regarding which pharmacokinetic parameters are most relevant for the use of IgG in PIDD patients, the FDA faced a quandary in formulating criteria for licensing IgG preparations to be given by the SC route.17 To be sure that patients being given SCIG were at least as well protected as those receiving IV preparations, the FDA took the conservative position that the AUC for SC IgG must equal the AUC for the previous IV regimen given to the same patient.17 In contrast, European regulators require only that the trough serum IgG level on SC IgG exceed that achieved on IVIG.18 For the one IgG preparation currently licensed for SC use in the United States, the requirement for equivalence of the AUCs resulted in a dosage penalty of 37%.12 That is to say, to achieve the same mean AUC for IgG given SC as compared with IV, an average of 37% more IgG had to be given by the SC route. It is not clear from published studies that equivalence of the AUC is necessary for therapeutic equivalence, and results of a European study in which the same dose was given by the IV and SC routes showed no difference in rates of infection (efficacy) from the North American study in which the SC dose was raised by 37%.12,13 In that European study, the mean steady-state serum IgG concentration achieved on SC IgG was 11% higher than the mean trough IgG concentration with the same total monthly dose being given once every 3 to 4 weeks by the IV route. In contrast, in the North American study with the 37% dosage increment, the mean steadystate IgG level on SC therapy was 32% higher than the mean IgG trough level on IV therapy.12 Data from these and other studies comparing IgG levels achieved by the IV and SC routes are presented in Table 1. The systemic adsorption of IgG from SC sites is considerably slower than that of IVinjected IgG. Sample pharmacokinetic curves for each route of administration are shown in Fig. 1. As seen on the left, an IV infusion of 406 mg/kg of IVIG into a patient who had X-linked agammaglobulinemia rapidly raised the serum IgG level by more than 900 mg/dL. The peak IgG typically decreases somewhat over the next 48 hours as the IgG redistributes into the total extravascular volume, then continues to decline with first-order kinetics and a half-life of about 22 days.19,20 Thus, patients on typical regimens of IV infusions every 21 to 28 days are never really at a steady state. During the course of each dosing interval, their serum IgG concentration typically varies by more than 700 mg/dL around the mean (in this case, 850 mg/dL). In contrast, when the IgG dose is fractionated into three or four equal doses given SC at weekly intervals, the slow systemic adsorption from the injection site or sites increases the serum IgG even as the IgG is diffusing out of the circulation elsewhere in the body. Thus, the peak is markedly truncated. Fractionating the usual 21- or 28-day IV dose into SC doses given weekly, or even more frequently, can result in a true steady state, in which the IgG being adsorbed from SC injection sites essentially replaces that fraction of the previous dose that has been metabolized. The right side of Fig. 1 shows data for the same patient maintained on a weekly SC dose equal to 40% of the previous 21-day dose; in other words, a monthly dose 20% higher than on IV therapy. The

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Table 1 Comparison of serum IgG concentrations on intravenous and subcutaneous therapy IV Dose (mg/kg/mo) 553 465 551 Mean IV Trough (mg/dL) 997 785 836 1051 Mean SC Dose (mg/ kg/wk) 138 158 89 138 SC Dose (as % of IV) 101.5 136.0 101.0 100.0 Mean SC trough (mg/dL) 1144 1040 922 1168 % D in Trough (SC/IV L 100%)a 14.7 32.0 11.0 11.1

Author (Y) Chouksey (2003) Ochs (2006) Gardulf (2008) Desai (2008)
a

(N) 5 51 47 10

Mean of individual percent changes.

maximum variation around the mean serum IgG concentration of 816 mg/dL is only 50 mg/dL. Fig. 2 shows mean serum IgG levels in 47 patients midway through a 6-month study in which they received an average weekly dose of 89 mg/kg IgG given SC on days 0 and 7 of the time period shown. Again, it is readily apparent that a near-steady state is achieved, with little variation in the IgG level over the 14-day interval sampled here.21 In a much earlier study of 23 adult CVID patients by Waniewski, and colleagues,22 it was reported that weekly SC infusions of 100 mg/kg maintained steady-state IgG levels, with little variation around the mean for more than a year. The time to reach this steady state was also examined in that study. One group of 6 patients, nave to IgG therapy, with a mean baseline IgG concentration of 220 140 mg/dL, was started on 100 mg/kg IgG SC once a week. After 6 months of weekly infusions, these patients

1600

30 gr 5% IVIG (406 mg/kg) Q 3 weeks

12 gr 16% ISG Q 7 days = 36 gr in 3 weeks

1400

1200

Total IgG

1000

800

600

400 0 2 4 6 8 10 12 14 16 18 20 22 0 7 14 21

Days

Days

Fig. 1. (Left) Serum IgG levels in a 34-year-old X-linked agammaglobulinemia patient while on a regimen of 30 g IVIG (406 mg/kg) every 3 weeks. (Right) After a few months on 12 g SCIG once a week.

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Fig. 2. Mean steady-state IgG levels in a group of 47 patients receiving weekly SC infusions on days 0 and 7.

had a mean serum IgG level of 820 180, which was still lower than the apparent steady state of 990 60 mg/dL achieved at 12 months of therapy.22 That concentration then remained fairly constant over 6 months of further treatment with the same weekly dose of SCIG.22 To obviate the slow and gradual rise in the serum IgG level observed in nave patients given only one infusion a week, Waniewski and colleagues22 gave another group of patients 100 mg/kg infusions daily for 5 consecutive days. That group of patients achieved a steady state of approximately 1200 mg/dL by the end of that 5-day course of treatment, and had mean levels of 1150, 1110, and 1120 at 6, 12, and 18 months later, respectively. It may be important to note, however, that the later group of patients had received IM or IV IgG treatment at unspecified times before beginning on SC treatment, and that they had a mean IgG level of 670 280 mg/dL just before beginning SC therapy. Nevertheless, many immunologists consider five to seven daily infusions of 90 to 120 mg/kg each satisfactory for quickly bringing up the serum IgG level of a newly diagnosed antibody-deficient patient, so that the patient can then continue on weekly infusions alone.23 In the recent pivotal study of an IgG preparation now licensed by the FDA for SC administration in the United States, patients who were already on stable IGIV treatment regimens were given their initial SC infusion 7 to 10 days after their most recent IV infusion; then, SC infusions were continued on a weekly basis. That schedule results in initially higher IgG levels for the next several weeks, which trend downwards over time to a new steady state. Desai and colleagues11 have also completed a recent study using that interval between the patients last IV and first SC infusions, followed by weekly SC infusions of one quarter of the previous monthly IVG dose (on a mg/kg basis). In those patients, the mean steady-state serum IgG concentration on SC infusions was 11% higher than the mean trough level had been on IV therapy, and that steady state was reached after 10 to 12 weeks of SC treatment.
ADVERSE EFFECTS Systemic Adverse Effects

The difference between the shapes of the pharmacokinetic curves illustrated above for SC versus IV IgG administration underlies one of the most important differences between current IV and SC regimens. Many of the adverse effects associated with IV infusions, such as headaches, fever, and anaphylactoid reactions, occur during the infusion or within 48 hours of it, while the serum IgG concentration is rapidly increasing or is still near its peak. Elimination of the sudden, rapid increases and transient peaks in the serum IgG concentrations is believed to be responsible for the marked amelioration in systemic adverse effects experienced by patients who transition from IV to SC regimens.24 One of the original rationales for using slow infusions

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when the IM preparations were given SC was that if large injections of IgG induced the release of mediators such as prostaglandins or cytokines, which produced chills, fever, and other remote systemic adverse effects, then slow administration might decrease the rate at which these putative mediators were released and would decrease their concentrations at any point in time,2 which, in turn, would allow compensation by normal homeostatic mechanisms. Indeed, many of the systemic adverse effects associated with IV infusions are considered rate related and may be obviated by slowing the rate of the IV infusion.25 With SC administration, a depot is created in the tissues, from which the IgG reaches the blood stream much more slowly than if it was infused directly into a vein. Furthermore, the serum IgG level remains nearly constant on SC regimens. Hence, rapid release or dramatic systemic effects of any mediators are unlikely to be produced when the exogenous IgG comes into contact with Fc receptors or antigens. The freedom from systemic adverse effects with SC administration was apparent when the first few reports of slow SC infusions of IM immune serum globulin (ISG) appeared in the early 1980s,26 and continues to characterize SC administration24 In the reports of Gardulf and colleagues9,26,27 in the early to mid-1990s, systemic adverse reactions were reported with less than 1% of SC infusions, as opposed to 46% with the IV preparations available in that era. Pac and Bernakowska8 reported a series in which 15 patients received 780 SCIG infusions over a 13-month period. Systemic adverse effects were experienced by only 1 patient, a child who had required steroids and other premedications before IVIG infusions. Although that patient tolerated the SC infusions for months with no problems, she subsequently suffered systemic reactions at two consecutive SC infusions, and was switched back to her previous regimen of IV premedication before standard IVIG doses. None of the other patients had significant systemic adverse effects and none switched back to IV therapy.8 In only two major studies has the incidence of systemic adverse effects accompanying SC infusions been reported as greater than 1%. Chapel and colleagues7 reported that 3.3% of SC infusions were accompanied by systemic adverse effects, as compared with 5% of IV infusions. Ochs and colleagues12 reported that headaches occurred during, or within 48 hours following, 1.6% of SC infusions, but only 35% of these headaches were considered severe, requiring prescription medications. Only 3 subjects out of 68 withdrew from that year-long study because of infusion-related adverse effects; no infusion-related serious systemic adverse reactions occurred.12
Local Adverse Effects

Most patients experience some kind of local reaction, at least transiently, at the sites of SC infusions. These reactions may include swelling, redness, and a sensation variously reported as itching or burning.11,12,24,28 The swelling may exceed that expected from the volume of fluid injected at the site, but that is unusual. Pruritis, when it occurs, is not usually severe. The patients sensation is often more just an awareness of the presence of an area of swelling or redness, rather than true discomfort. In the trial of Ochs and colleagues,12 these reactions occurred initially in nearly 90% of patients, and were mostly considered mild or moderate (Fig. 3). Only 3 patients out of 68 discontinued participation in that study because of local site reactions. In almost all cases, local swelling or redness dissipates within hours (Fig. 4). Occasionally a small, pearl-sized nodule or knot may persist for 1 or 2 days. Examination of patients who have infused IgG SC in the same region of the body (ie, anterior abdominal wall, flanks, or upper thighs) for years has not revealed any long-term changes such as fibrosis or fat necrosis. In most studies, the incidence of local reactions has been reported to decrease over several months of continuing SC

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Fig. 3. Local site reactions in a SC IgG licensing trial. (Top) Mild reaction; slight erythema with minimal swelling. (Bottom) Moderate reaction; significant swelling. Swollen area is blanched and surrounded by a ring of erythema few millimeters in width.

therapy, as illustrated in the data of Ochs and colleagues (Fig. 5). Most of the data on which that and similar curves are based are recorded by the patients in diaries they keep at home. Therefore, it is likely that a major contribution to the recording of the reactions is subjective. As the patients get accustomed to the local phenomena that accompany SCIG infusions, they are less likely to report a small degree of local swelling as a reaction. It is possible that the decreased rate of local reactions associated with SC infusions might represent some kind of accommodation of the patient to the specific product, which might be analogous to the increased rate of reactions associated with switching to a new IV preparation reported in some studies. Biopsy studies of SC IgG infusion sites at various times after the injections have not been reported.
Wear-Off or Trough Effects

As opposed to acute adverse effects associated with the high peaks of IgG in the serum that accompany bolus IV administration, many patients who receive IVIG infusions every 21 to 28 days report general malaise, fatigue, arthralgias or myalgias, and increased susceptibility to infections during the last 7 to 10 days of each dosing interval. Most patients on IV treatment regimens report that they can feel their IVIG wearing off before their next infusion is due.29 Often, patients will report that they have run out of gas or feel punk at the end of the IV dosing interval. It is apparent from the graphs that these low serum IgG levels are obviated by weekly or more frequent SC infusions. Table 1 summarizes the changes in trough serum IgG level on SC versus IG therapy reported in several recent studies. As patients achieve stable steady-state serum IgG levels on SC regimens, they frequently report alleviation of

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Fig. 4. Clearing of local site reactions after SC IgG administration. A 14-year-old girl has just finished infusing approximately 22 mL of a 15% solution of Carimune into each of two abdominal sites sequentially. The infusion into the first site (to the patients left of umbilicus) was given over about 1 hour and ended 1 hour before the picture was taken. The site of the needle is still visible, as is some diffuse swelling, but the redness has almost completely dissipated. The infusion into the second site (to the patients right of umbilicus) was just completed before this picture was taken. Note the mild central swelling surrounding the needle site, and several centimeters of redness, but no induration per se. The patient was infused with 6 g of 15% Carimune solution made by pushing 40 mL of sterile water for injection into a 6-g bottle of lyophilized IgG. Note that indented scars are from surgical drains or other procedures, not from IgG infusions.

the symptoms they previously experienced as their serum IgG levels approached their nadir. This improvement, in turn, may lead to an overall more continuous feeling of good health, which likely contributes to the increased quality of life reported by most PIDD patients who switch from IVIG to SC.27,3032

QUALITY-OF-LIFE EFFECTS

Several formal studies have been done of the health-related quality of life of PIDD patients on different modes of therapy, mostly performed by Gardulf and colleagues in Sweden. European and North American patient populations have been surveyed for these studies. PIDD patients in the United States have also been surveyed by the Immune Deficiency Foundation (IDF), but that survey was completed before any SC product was licensed in the United States. Several sources of dissatisfaction expressed by patients in the 2003 IDF survey are directly related to the sites, timing, or frequency of IV infusions. The specific sources of dissatisfaction with IV regimens resonate with the results of the studies of Gardulf and colleagues, and can be affected by switching from IV to SC therapy. Most importantly, although 64% of PIDD patients surveyed by the IDF reported that they were somewhat or very satisfied with the convenience of the location of their IVIG treatments, satisfaction was reported by 96% of patients infused at home, as compared with only 51% of those infused in doctors offices and 48% of those infused in hospital outpatient clinics. Among those infused in other locations, only 39% reported that the location was very convenient. Sixty-nine percent of the patients reported receiving their IVIG infusions on weekdays between 9 AM and 5 PM, and only 64% considered that very convenient. Eighty-eight percent of patients reported receiving IVIG infusions at intervals of 3 weeks or longer,

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Fig. 5. Incidence of local site reactions during SCIG therapy. (Data from Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of self-administered SC immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol 2006:26:265.)

but 68% reported that usually or sometimes they could feel the effect of their IgG wearing off before their next infusion. Over the course of a patients lifetime, these sources of dissatisfaction can become major burdens, with significant emotional consequences.27,32 Many of the sources of dissatisfaction with IV treatment regimens can be alleviated by switching to SCIG. Because of the safety of SCIG and the fact that IV access is not required, most patients can be infused at home, either by a parent or partner, or by self infusion, and assistance by trained medical professionals is not routinely required. Infusions can therefore be given on a schedule of the patients own choosing. Because the infusions in most SC regimens are given weekly or even more often, and a true steady state is achieved, wear-off effects are also obviated. In their 2004 study of patients in Europe receiving SC IgG infusions at home, Gardulf and colleagues30 used standardized instruments for recording health-related quality of life. These included the child health questionnaireparental form 50 for children and the short form 36 for adults. In addition, a life quality index form was developed to examine the patients perceptions of the impact of their IgG treatment on their daily activities.3032 Among children previously receiving IVIG infusions in the hospital, significant (P <. 01) improvements in 6 out of the 14 subscales were reported after 10 months on weekly SC infusions at home. Of these, improvement reached significance within 6 months of home therapy on the scales measuring general health perception, emotional impact, family activities, and global health.30 For adults who had previously been on IV therapy in hospital, the switch to SCIG at home resulted in improvements in the vitality, mental health, and social functioning scales. Treatment satisfaction increased in both children and adults, and all the children and 73% of the adults preferred SC over IV treatment.30 In a similar study applying the same survey instruments to North American patients, children and adults who had been on IV infusions in hospitals or doctors offices before switching to weekly SCIG at home recorded significantly (P < .01) higher scores for scales measuring rolephysical (extent of limitation in normal activities [schoolwork and so forth] due to physical problems), general health, vitality, and health transition (improvement) after 12 months on SCIG at

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home.31 Even more dramatic (P<.001) changes were reported in treatment satisfaction, including decreased interference of treatment with other activities, decreased problems related to receiving therapy, and increased satisfaction with the treatment setting.31 In contrast, among patients who were receiving IV treatment at home before entering the study of SCIG, significant improvement in only one scale, general health, was reported. These results suggest that major improvements in quality of life are achieved when PIDD patients are treated at home rather than in hospitals or doctors offices. SC infusions facilitate a transition to home care because of their freedom from adverse effects and the lack of a requirement for trained medical personnel. Elimination of the low trough levels just before monthly IV treatments, which obviate periodic increases in susceptibility to infection, is probably responsible for the increase in general health reported by all patient groups on switching to SCIG, regardless of the location at which the treatment was administered. These conclusions are further supported by the patients preferences: 76% of the patients in the North American study expressed a preference for SC rather than IV therapy, whereas 91% of the patients preferred home treatment.31 Despite the apparent advantages of home SCIG treatment for most PIDD patients, not all patients are interested in switching from IV to SC treatment, and not all patients want to switch from hospital or office to home treatment. In Germany, where home SC has been offered as an alternative to IV treatment since 2003, demographics and attitudes were recorded from 32 adult patients who chose SC therapy and were compared with those recorded by 28 adult patients who chose to remain on IV therapy.10 Patients who chose SC treatment were younger (37 9 versus 51 14 years of age, P < .001) and a higher percentage were employed (69% versus 28%). The predominant reasons patients on IV refused to try SCIG were perceived inconvenience (48%), anxiety about adverse reactions at home (31%), and anxiety over needle sticks (6%). In contrast, the major reasons patients on SC gave for preferring that route were flexibility (50%), decreased side effects (17%), and constant IgG levels (17%). Thus, in considering which route and location of therapy might be most appropriate for any given patient, it is important to consider the individual patients life situation and attitudes toward self versus assisted treatment, and the medical advantages and disadvantages of each route for that individual patient. Although SCIG may be preferred by many PIDD patients, it is not necessarily the best choice for everyone.
PATIENTS WHO HAVE SPECIAL CONDITIONS

Only a few reports exist of the use of SCIG in PIDD patients presenting unique challenges for IgG therapy, including pregnancy, IgA sensitization, and bleeding disorders. The author and his colleagues original motivation for using ambulatory pumps for slow SC delivery of IgG was to facilitate adequate IgG replacement in a pregnant patient who did not tolerate IM injections or plasma transfusions. At times during the third trimester, that patient self administered 140 mL of 16% IgG per week, equaling 22.4 g per week.5 The patient gave birth at term by a spontaneous vaginal delivery, and neither mother nor baby suffered any complications of the therapy or delivery, nor any postpartum problems. Mothers and babys IgG levels were 620 mg/dL and 880 mg/dL, respectively, on day 2 after birth.5 Gardulf and colleagues33 subsequently reported a series of 11 pregnancies in nine immunodeficient women who self infused 100 mg/kg/wk at home throughout the pregnancies, using a rapid infusion protocol. No complications or serious infections occurred, and in all cases, the cord blood IgG concentration was equal to, or higher than, the mothers. No reports have been published describing large series of infants who had antibody deficiency treated

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with SCIG, but several pediatric centers have been administering IgG in this way because the difficulty of obtaining IV access, which is common in babies under 2 years of age, is obviated with the SC infusions. The author and his colleagues have treated several patients in this age group with SCIG, and have found weekly doses in the range of 1 mL of 16% IgG (160 mg) per kg, up to 10 mL, are easily tolerated in the thigh. Although some parents may be hesitant to poke their baby, once they see how well the babies tolerate the small prick of a single 27- or 28-gauge needle, they are quickly relieved. Especially if previous attempts at IV therapy have required multiple sticks or the use of scalp-vein infusions, the advantages of the SC route are readily apparent. Many physicians and patients inquire about the use of the SC route in patients who have bleeding disorders or anticoagulant therapy. Heparin is commonly self administered at home by the SC route and, although some local bruising may occur, bleeding from the sites is usually not a significant problem. Arora and colleagues34 have reported the use of SCIG in a patient who had von Willebrands disease with no special precautions or problems, and anecdotal reports exist of the successful use of SCIG in boys who have classic hemophilia. Another concern that is frequently voiced about IgG treatment of PIDD in general, both IV and SC, is the potential for problems associated with administering IgAcontaining IgG preparations to IgA-deficient patients. Although a risk for anaphylaxis exists if preparations containing IgA are given to patients who lack that protein, in practice this event is extremely rare. Anaphylaxis due to SC injection of IgA-containing preparations has not been reported, and this procedure is generally regarded as safe in PIDD patients, most of whom have some IgA or also lack the capacity to produce IgE (ie, Brutons agammaglobulinemia). Sundin and colleagues35 have reported that administration of IgA-containing IgG preparations SC was well tolerated by patients who had detectable anti-IgA antibodies, although the isotypes of the anti-IgA antibodies were not reported and none of the patients were specifically tested for IgE against IgA. Four of the anti-IgApositive patients lost their anti-IgA activity after weeks to months of weekly treatment with an IgG preparation containing up to 5 mg/mL of IgA.35 Induction of a state of unresponsiveness to IgA was inferred from the absence of IgA-containing complexes in the patients sera and the lack of reemergent anti-IgA activity, even after switching to low-IgA preparations.35 The presence or absence of partial IgA deficiency does not seem to correlate with local reactions to SCIG, or with the amelioration of these reactions over time. Because of the theoretic risk for anaphylaxis, anaphylactoid reactions, and other severe averse effects, it is recommended that the initial doses of SCIG always be given in a clinical setting equipped to treat acute severe reactions in the unlikely event they occur.21
COST

Comparisons of the costs of SC versus IV therapy regimens in the early 1990s reported that substantial savings were achieved by the use of IM preparations by the SC route.26 Analysis of that data suggests that the savings were mainly due to decreased cost of the stocks of IM ISG compared with the (at that time) new IV preparations. In the current era, the major cost of any IgG treatment regimen is the product itself. In turn, the single biggest contribution to the cost of the products is the cost of the starting plasma itself. Although marketing and distribution expenses vary, in general, the costs of SC and IV products supplied by most manufacturers are, and will likely continue to be, in the same range. Typical regimens for selfSC administration at home generally use one or more pumps, which may have purchase prices ranging from a few hundred to a few thousand US dollars each. Depending on arrangements

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for purchase or leasing of the pump or pumps, service charges or amortization of the purchase price may add as much as $50 to $100 a month to the cost of SC regimens. Several popular pumps require special, proprietary syringes or tubing sets, which may add $5 to $25 to the cost of each infusion, and elaborate multibranched tubing sets with special SC needles may also drive up the per-infusion costs. Because infusions are typically given once or twice a week, the cumulative annual costs of some regimens may be considerable. In contrast, many IV regimens include facility fees or bed charges, and charges for the nurse or other health professional who starts the IV and monitors the infusion. IV infusions are frequently given using pumps for precise control of the infusion rates, which may add an equipment charge or purchase price to the cost of the IV regimen. Because IV regimens typically involve infusions that are given only once every 3 or 4 weeks, those costs may not accumulate as rapidly as the cost of the supplies associated with SC regimens. Indirect costs, such as for transportation to a hospital or infusion center, parking, and time lost from work, should also be considered in comparing the total costs of home SC versus hospital- or officebased IV treatment regimens. A recent study performed by the Canadian Government Agency for Drugs and Technologies in Health (CADTH) concluded that home IV treatment would be the least expensive program for PIDD patients in that country, with home SC a close second. The estimated direct yearly per-patient costs for treating an average adult who has IVIG in hospital was C$ 21,777; IVIG at home (self administered, without a nurse) was C$19,891; and SC at home was C$ 20,416. When indirect costs, such as transportation and time lost from work were included, the costs were C$ 23,037 for hospital-based IV, C$ 20,302 for home IV (assuming this would be self administered, without a nurse), and C$ 21,033 for self-administered home SCIG. However, when the decrease in adverse effects and increased quality of life with SC versus IV treatment were included in the calculations, the conclusion was reached that SCIG dominates because of greater expected benefits at lower expected costs per quality adjusted life-year.36 Overall, if the 75% Canadian PIDD population now receiving IgG treatment switched from IV to SC therapy, the CADTH estimated that the savings to the government would be approximately C$ 9,000,000/y.36 This analysis assumed the same price per gram of IgG regardless of the route by which it would be administered. A similar analysis in Germany, using actual data on payments by insurance companies for PIDD patients receiving IgG by both routes, showed that the average price per gram for IgG to be given by the SC route was only 46% of that for IgG to be given by the IV route. Overall, the budget impact analysis from that study, independent of any adjustment for improvement in quality of life measurements, showed that yearly savings for the German statutory health insurance would be 17 to 77 million Euros annually if 60% of current PIDD patients switched from IV to SCIG.37

PRACTICAL CONSIDERATIONS IN SUBCUTANEOUS IMMUNOGLOBULIN THERAPY FOR PRIMARY IMMUNE DEFICIENCY DISEASES Selection of Infusion Regimens

The author and his colleagues initial attempts to give SC IgG infusions were performed using 16% ISG preparations in a patient who previously had demonstrated poor tolerance for IM injections of the same preparations.2 Other early patients were usually also chronically infected. To avoid local or systemic adverse effects, they administered the ISG slowly, initially at 1 to 2 mL per hour.2,5 Furthermore, because the ISG was generally provided in 10-mL vials, that was the usual volume infused into a single site. As other investigators began to use this method in a wider

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spectrum of patients, it became clear that much faster rates and increased volumes per infusion site could be tolerated. In their 1991 study of 25 PIDD patients routinely receiving SCIG infusions for 1.25 to nearly 4 years, Gardulf and colleagues9 reported that those patients who had higher body mass indexes were receiving higher doses at each infusion, and using two pumps with up to four sites in the abdomen or thighs for each infusion. The mean volume per infusion was 42.8 mL (range 2860), and the mean duration of the infusions was 75.8 minutes (range 45120 minutes). Each patients initial infusion was given at a rate of 10 mL/h into each site. After several infusions, the rates were increased by 1 mL/site/h every few weeks according to each patients tolerance, until the above rates were acheived.9 Although 36% of those patients had previously suffered severe reactions after IM injections, no severe or moderate reactions were observed after the SC infusions, and only 0.9% of SC infusions were accompanied by mild systemic symptoms.9 Subsequently, Gardulf and colleagues26,38 continued treating patients with these rapid infusions at 20 to 40 mL/h. Similarly, Gaspar and colleagues39 reported the routine use of 20 mL/h, usually into two sites simultaneously. Hansen and colleagues40 then reported that most patients tolerated express infusions at rates up to 35 mL/h/site, such that 10 mL could be delivered per site in 17 minutes. Using multiple syringe drivers to deliver IgG into four sites simultaneously, these investigators reported that 40 mL (6.4 g of IgG) doses were routinely tolerated in as little as 17 minutes.40 In the only licensing trial of SCIG that has been reported in the United States, limits were set at 20 mL of IgG per hour with a maximum of 15 mL/site.12 In studies of this type, conservative regimens are often selected for fear that adverse effects, if they occur, will have a negative impact on the regulatory authorities. It is therefore likely that similar rates and volumes per site will also be selected in future pivotal studies. In contrast, when IgG preparations marketed for IV or IM use were used off label for SC infusions using drivers that could accommodate syringes as large as 60 mL, a much broader range of regimens could be used, and the flexibility of the SC route could be exploited more fully. Taking into consideration the patients preference as to the number of needle sticks (sites) per infusion and the time he/she is willing to spend, it becomes readily apparent that these two variables have a reciprocal relationship. That is, if more sites are used, the overall time for infusing a given total dose will be decreased as compared with giving the same dose into fewer sites. Additionally, it becomes readily apparent that fully grown adults can tolerate greater volumes per individual site than small children, and that it is likely that patients who have greater amounts of SC tissue (ie, higher body mass index or obese individuals) will also tolerate more IgG per site than lean individuals. If infusions are given slowly, then the infused IgG may be diffusing away even as more is being given, so that more volume can be put into an individual site without increasing the local discomfort or severity of any possible reaction. Before any SC preparation was licensed in the United States, the author and his colleagues reviewed the SC regimens being used by their patients, most of whom had been referred because of adverse effects with IVIG. These patients were receiving SC infusions of an IM ISG preparation, or a lyophilized preparation reconstituted to yield a solution with an IgG concentration of approximately 15%.41,42 Regimens ranged from 10 mL into one site in less than 1 hour in children, to 40 mL over several hours into one site (usually taken at night while the patient was sleeping), to 40 to 60 mL given into multiple sites simultaneously in short times. The spectrum of regimens eventually selected by the patients, who ranged in age and size from preemies initially weighing 5 kg to adults weighing over 130 kg, was broad but could be inclusively summarized by calculating the rate in mL of IgG per site per hour per kg body weight. The mean was found to be 0.176 mL/site/kg/h,

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with a standard deviation of 0.134,42 which is approximately equal to 12 mL/site/h in an average 70-kg adult, or 3.5 mL/site/h in an average 20-kg 6-year-old child. The flexibility illustrated by the regimens discussed above suggests that the patient should have a major input into designing his/her own regimen, according to his/her preferences, tolerance at the local sites, and lifestyle choices. The patients priorities for the number of infusions per month, number of needle sticks, and time per infusion can be easily accommodated if the regimen is selected thoughtfully. A useful algorithm is to determine the total IgG dose to be delivered per month and to ask if the patient already has firm ideas about the regimen he/she would like to use. If the patient does not, a good starting point is to divide the total volume of IgG to be infused during the month by four and to start with the assumption that one infusion per week will be preferred. The volume to be infused weekly can be rounded off to the nearest multiple of whole vials of IgG product, so that the patient can be taught to draw up each dose without wasting any of the IgG and without requiring a pharmacist to be involved. The number of pumps that will be available to the patient should then be considered. In most cases in the United States, a patient is likely to have only one pump at home, whereas in the United Kingdom, it is common for the National Health Service (NHS) to provide two pumps to each patient.43 In Sweden, up to four pumps are frequently used for each infusion. Dividing the volume to given in each infusion by the number of pumps narrows the choices of the size of the syringe that will be used for each pump, which, in turn, is a major factor in determining which pumps might be used for that particular patient.44 The number of sites to be used for each infusion and the time can then be calculated based on the patients preferences. The calculated value given above, 0.18 mL/kg/site/h, can serve as a useful guide and starting point. The product manufacturers recommendations in the prescribing information can be used in the same way, but it should be remembered that such information has usually been selected in an arbitrary way to facilitate uniform data collection during clinical trials. Once an initial regimen plan is formulated, it should be reviewed carefully with the patient to be sure it is acceptable and the patient does not foresee any problems in complying with it. If the time, number of sites, or volume per site in the planned regimen seems excessive, splitting the dose into two or more infusions per week should be considered. Orders can then be written and the appropriate equipment obtained. As the patient becomes experienced with the infusion regimen, it can be modified. In many cases, the patients tolerance of local site reactions increases with repeated infusions, and the time for each infusion can be shortened or the volume of IgG infused per site can be increased. The paragraph above describes a reiterative process that may be used to arrive at an optimal regimen, individualized for each patient, and is based on the experience in the authors clinic with various patients and multiple different IgG products over many years. Each of the parameters in Box 1 may be considered independently, and varied to reach a regimen that fits easily into each patients individual lifestyle and preferences. Some investigators have explored options at the extremes of the above regimens. For example, Shapiro in Minnesota and Ochs in Seattle have reported anecdotally that many patients prefer to increase the parameter of the number of infusions per month out to 20 to 30, by giving daily pushes of 10 mL each, which is done conveniently by repeatedly pushing 1 to 2 mL from a 10-mL syringe without any mechanical pump at all. Daily doses of 10 mL (1.6 g, if a 16% IgG solution is used) are easily given over 5 to 10 minutes in this way, and are well tolerated by many patients. Infusing 1.6 g every weekday gives a monthly dose of 35.2 g, and the patient does not have to take infusions on the weekends. In contrast, if the patient takes a 1.6-g infusion every day, the total monthly dose will be 48.8 g per month.

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Box 1 Establishing an optimal subcutaneous immunoglobulin regimen for any individual patient 1. Predetermination: dose of IgG in mg/kg/mo. Start with estimated dose of 500 mg/kg/mo, use current monthly IV dose, or use current monthly IV dose correction for bioavailability if desired. 2. Parameters that should be selected in accordance with patients preferences. Note that any individual parameter in this list can be prioritized and set as the most important variable, which will influence the choices for the other parameters. Number of infusions per week or month Volume per infusion Number of sites per infusion Volume per site Total time for each infusion Decision to use multiple sites simultaneously or sequentially Number of pumps

At another extreme, patients may prefer only a single needle stick per week and might choose to infuse a large volume into a single site, which may be accomplished over a long time using a pump that can drive a large (60-mL) syringe, or with a rollertype pump and a reservoir. Examples of this type of regimen include the author and his colleagues patients who infuse up to 60 mL at rates of 8 to 10 mL per hour while they sleep, and regimens reported by Dr. Charles Kirkpatrick of the University of Colorado, in which a single SC needle with a short pigtail tubing that can be closed and capped, is kept in place overnight. IgG is infused into that single site over 2 consecutive days, which would easily allow doses of IgG as great as 120 mL (19.2 g) to be tolerated by most patients each week. Another variation on a standard weekly dosing regimen was recently reported by Gustafson and colleagues,45 in which doses of 200 mg/kg were given SC every other week rather than 100 mg/kg every week. Trough IgG levels on the two regimens were not compared directly, but no increase in adverse effects (AEs) or infections was reported.45 An alternative approach is to adopt a simplified regimen using a rule of twos": "two bottles into two sites over 2 hours. For the average 70-kg adult, an infusion composed of two 20-mL vials of 16% IgG given in this way equals 10 mL per site per hour, or 0.143 mL/kg/site/h, well within the range described above. For a 35-kg child, the same rate per site is achieved if two 10-mL vials are used. These regimens provide 6.4 g or 3.2 g of IgG per infusion, respectively. The desired total monthly dose can then be achieved by varying the number of infusions per month. For example, two 40-mL infusions per week would provide 51.2 g per month, and two 20-mL infusions per week would provide 25.6 g per month. Given that any level of activity short of rigorous exercise or total immersion in water is possible while taking these SC infusions, 2 hours per infusion is easily tolerated once or twice a week by most patients, most of whom spend many more hours than that every day sitting at a desk or in front of a television or computer, doing housework, or walking at a moderate pace.
Site Selection and Specific Procedures

Numerous resources describe in detail exact procedures to be used in selecting and preparing sites and actually administering the infusions.43,4649 SC injections are most

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frequently given in the anterior abdominal wall out to the flanks, the anterior or inner thighs, and the backs of the upper arms; these are diagrammed in the cited literature. A useful and easy-to-remember guideline is to be able to pinch an inch of SC tissue at any intended site. A key to successful SC infusion is to place the needle sufficiently deep to avoid intradermal administration. Initially, the author and his colleagues used .75-inch 25-gauge butterfly needles inserted at a 45 to 90 angle to the skin. Now, various needles specifically designed for SC use, with the needle itself mounted at 90 to the wings or gummed disk and tubing are available.44 Except in the leanest patients, needles of 11 to 15 mm in length are preferable, to be sure the infusion is given into SC fat, and to minimize leakage from the site. When leakage or excessive redness occurs, it is often because needles that are too short (only 6 mm) have been used. Various stainless steel and silastic catheters in the range of 25 to 28 gauge and 6 to 15 mm in length are now marketed, attached to tubings of various lengths, with as many as four branches attached to one hub,44 for infusing into multiple sites simultaneously. For most patients, a simple antiseptic wipe with alcohol or chlorhexidine is all that is needed to prepare the site. Extensive scrubbing is not usually necessary, and repeated use of iodine-containing antiseptics such as Betadine may actually be irritating or cause sensitization. A eutectic mixture of local anesthetics (EMLA) has been successfully used with children and with adults who may have anxiety about sticking themselves, but it is generally not needed because the needles are so small and precise placement, as with IV catheters, is not necessary. Excessive or irritating tape should be avoided; many patients have more erythema and itching from the tape than they do from the SCIG itself. The most important precaution is that the patient should draw back from the needle with a syringe before starting the pump or pushing the product, because high-concentration IgG solutions intended for SC or IM use may not necessarily be free from dimers or larger aggregates, which can cause adverse reactions if injected intravascularly. Providers should remember to instruct patients in the proper disposal of sharps and other medical waste, and should make sure that proper containers are available and appropriate logistics have been arranged.
Initiating Subcutaneous Therapy/Teaching the Patient

Various publications and other resources are available for instructing patients to self administer SCIG, including illustrated brochures on Ig manufacturers Web sites,46,47 a monograph available from the IDF,50 a small pamphlet prepared by the National Institutes of Health Clinical Center nursing staff on how to give a subcutaneous injection,48 and additional information specifically written for patients that is available on the Web.43,49 Several organizations, including the American Academy of Allergy, Asthma, and Immunology, Case Western Reserve University/University Hospitals of Cleveland, and CSL-Behring, offer courses for physicians, nurses, and pharmacists, to assist with development of expertise within individual practices, institutions, and home care companies/specialty pharmacies. Centers in different countries have developed different approaches to actually starting SCIG therapy and teaching the patient, parent, or partner to perform the infusions when that is appropriate. Several of these are described in the book, Subcutaneous Ig Training and Education Program.23 Frequently, logistics, including the time necessary for obtaining approval from the patients insurance company and identifying the appropriate home nursing service/specialty pharmacy (when that is necessary), play a major role in determining the approach to be used in any given case. Most patients who have been referred to the author and his colleagues have already been on IVIG. Many other patients are newly diagnosed but not hospitalized, and it is desirable to get

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their IgG supplementation going without delay. In these situations, the author and his colleagues will submit the necessary paperwork for SC therapy while they start or continue the patient on IV infusions at their center. One or two 10-mL aliquots are removed from the total volume of IVIG to be administered, by drawing that amount out with one or more 10-mL syringes. These aliquots are then infused SC while the main part of the dose is being given IV. Anecdotal and published reports42,51 suggest that most IV preparations are well tolerated by the SC route. The nurse instructs the patient in how to administer the SC infusion and demonstrates as he/she starts it. The patient then experiences the sensation at the infusion site, and is given the opportunity to confirm that he/she would like to switch to the SC route. Another SC infusion is then started at a different site, and again, the nurse explains each step. That infusion may be stopped after 3 or 5 mL have gone in, and the patient is invited to start a new infusion at a different site using the IgG remaining in the syringe. In many cases, this step can be done two or three times during the course of a single IV infusion. After he/she has completed an instructional program and observed a nurse starting the infusions several times, the patient should demonstrate proficiency back to the nurse/physican. A checklist the nurse can initial to document that the patient has successfully mastered each step can be used to provide documentation that all necessary techniques were taught correctly. Medicare and Medicaid now have billing codes that will allow reimbursement for the time involved in starting and administering SCIG infusions (obviously, one cannot bill for SC and IV infusions at the same visit), and preapproval for the SC product and involvement of a specialty pharmacy are not necessary because the patient is actually receiving an IV product. Teaching the procedures for SC infusions is continued in the same way at subsequent IV infusion visits until the patient receives the pump, syringe, and product he/she will actually use at home for self/parent/partner infusions. When that occurs, the author and his colleagues ask the patient to bring those materials into their clinic so they can be instructed with the actual supplies they will use themselves. At that visit, it is not necessary to bill for the product, supplies, or pump because that has all been arranged and provided by the home care company/specialty pharmacy. The next time the patient is due for an SC infusion, usually 1 week later, the home care nurse is asked to go to the patients home and observe/instruct the patient on self infusion. More than one visit may be necessary, but that is not usually the case because the patient has already been instructed by the authors office staff. It may be helpful if the home care nurse or someone from the physicians office confirms that he/she will be accessible by telephone during the patients first several infusions at home, to provide reassurance or talk the patient through any step at which he/she has questions or difficulties. Finally, the author and his colleagues ask the patient to return to their clinic after he/she has taken a few infusions at home without a nurse present. The patient brings his/her product, pump, and supplies and gives him/herself an infusion under observation, to be sure all questions are answered, everything is being done in a sterile and safe way, and no problems are evident. After that, the patient continues on home infusions, and follow-up visits are scheduled as indicated by the patients medical condition. Other approaches include starting nave patients on IgG replacement by giving five to seven daily infusions in the hospital and using each days infusion as an opportunity for instructing the patient. This approach need not be limited to inpatients. Gardulf and colleagues in Sweden have had good success with conducting a 6- to 8-day course of instruction that covers not only the techniques for home SCIG administration but also basic information about PIDD, helpful instruction in hygiene for PIDD patients, and other relevant matters. This course is given to small cohorts of newly diagnosed

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patients who come together at the referral center when the course is given. The patients within the cohort have the ability to bond with each other, and then they continue as a support group for each other after the formal instruction period is completed. In other settings, 24-hour availability of an on-call nurse or pharmacist accessible by a toll-free phone number, or identification of an infusion buddy, who either takes his/her own infusion together with another patient or is available by phone, will provide an additional level of comfort and confidence to patients who have any degree of anxiety or hesitation about proceeding at home. It is important, particularly for patients who are used to being seen by the physician at every visit when IV infusions are given in the office setting, to be instructed carefully about potential problems with their infusions and complications of their underlying PIDD that should cause them to contact their physixcian urgently, or when to go to an emergency room or urgent care facility. Although most practices in the United States will prescribe preloaded epinephrine injectors (such as an Epi-pen) for patients who infuse IgG at home, in fact, these are rarely needed for patients using the SC route. The United Kingdom NHS now no longer provides these for home SC patients because they were so rarely actually needed. Finally, patients who are self infusing at home should use special medical waste (biohazard or sharps) containers and should discard needles or other used medical equipment cautiously. In addition, provisions for collecting and appropriate disposal of the waste containers must be arranged.
Assuring Adherence to Subcutaneous Regimens

In many cases, patients on home SCIG regimens will be seeing the physician or other health care professionals less often than previously, especially if the patient had been receiving IGIV in the physicians office and a check-up at each infusion visit. Patients should be carefully evaluated for reliability and insight before they are allowed to have the degree of independence possible with home SCIG regimens. As with all other users of blood products, patients should keep a logbook in which the infusion date, lot number, and expiration date of all vials of IgG are recorded. If the patient wants to keep this log electronically, it should be carefully backed up onto a disc or other memory device separate from the computer itself, or forwarded to a central memory service. Inspection of the logbook or computer record by the physician or nurse at regular intervals should be an important part of each patients follow-up. An additional precaution may be to ask the patient to mark the label of each vial of IgG with the date on which it was used, and then to return the empty vials to the physicians office. Because the serum IgG concentration tends toward a true steady state if SCIG is given weekly or more often, the patients serum IgG can be drawn randomly, and should serve as an indicator of compliance with the prescribed regimen. However, changes in metabolism accompanying different disease states, or protein losses, for example, due to nephropathy or enteropathy, may be the cause if low levels are observed. In growing children, the dose or regimen may need to be altered every few months as the child gains weight.
SUBCUTANEOUS IMMUNOGLOBULIN IN OTHER CONDITIONS

Although the SC route has proved to be useful for delivering the doses of IgG used for replacement therapy in PIDD, few studies have been carried out of the use of this route in autoimmune and inflammatory diseases for which doses in the range of 1 to 2 g/kg are given over 2 to 4 days once a month. It should be obvious from the data in Fig. 1, in which a hypogammaglobulinemic patient sustained an increase in his serum IgG

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concentration of more than 800 mg/dL when he was given 400 mg/kg of IGIV, that patients receiving doses in the range of 1000 to 2000 mg/kg over 1 to 4 days will reach extremely high IgG concentrations. These IgG levels can significantly increase blood viscosity and may be associated with increased risks for ischemic, thromboembolic, and renal adverse effects.52 Fractionating the same monthly dose into 10, 20, or even 30 aliquots, which could be given at 1- to 3-day intervals throughout the month, might be expected to decrease the maximum IgG level and the alterations in blood rheology and might, therefore, be safer. Furthermore, patients who are receiving "high-dose IGIV therapy are usually monitored closely during their infusions, so they are frequently treated in hospitals or infusion centers rather than at home. It therefore seems likely that SC infusions would be particularly preferable for many patients in terms of safety and convenience. Multiple mechanisms of action have been proposed to account for the efficacy of high-dose IGIV in autoimmune/inflammatory diseases, and it seems likely that different mechanisms are important in different disease states, depending on their pathophysiology.53 In any disease state in which an extraordinarily high peak is not required, the SC route would seem likely to offer distinct advantages for many patients. Even in the authors initial experience with SCIG in the early 1980s, it became obvious that a motivated patient (a young woman who wanted to safely carry a pregnancy through to term) could take two 10-mL SC infusions every day, yielding a monthly dose of nearly 100 g.5 Current regimens for PIDD frequently have patients taking as much as 60 mL of 16% IgG (9.6 g) over 1 to 2 hours while they are performing normal activities. Because this regimen is well tolerated, or even preferred over IV infusions, by most patients, no a priori reason seems to exist as to why multiple infusions in that dose range could not be given several days per week. Few studies have been carried out of SC dosing in this range for the treatment of autoimmune/ inflammatory diseases. In one report of SCIG in patients who had well-documented chronic idiopathic demyelinating polyneuropathy (CIDP), one patient who could not be successfully treated with immunosuppressive medications and had only transient responses to IGIV doses of 800 mg/kg was successfully transitioned to SCIG. This patient, a 73-year-old woman weighing 75 kg remained stable with good strength for more than 8 months on a regimen of 16 g of IgG per week, given as five separate infusions of 3.2 g (20 mL) over 2 hours each. The other patient, a 53-year-old man who also could not be successfully treated with immunosuppressive and IGIV therapy, has been successfully managed for more than 2 years with only 6.4 g of IgG per week, given as a single infusion of 40 mL of 16% SCIG.54 Neither of these patients had any side effects from the SC infusions other than local swelling; no systemic adverse effects were reported at all.54 In the first patient, the cost savings associated with the use of SCIG rather than IGIV was estimated at 30,000 Euros per year. Cost savings were not estimated for the other patient. Koller and colleagues55 have reported on three patients who tried the SC route to receive IgG for neuromuscular diseases. One patient developed a systemic exanthem after 9 weeks on SCIG and refused further treatment by that route. Another patient, with biopsy-proven CIDP persisting for more than 2 years, previously suffered multiple relapses despite corticosteroids and IGIV. He was successfully managed with weekly infusions of 100 mg/kg of SCIG and showed marked reduction in disability scores over the 6 months described in the report. No further relapses occurred and his steroid dose could be reduced. The third patient had multifocal motor neuropathy that had responded in the past to IGIV. He was also successfully managed with 100 mg/kg of SCIG per week and did not require any other therapy. It thus seems clear that, although SCIG cannot be widely recommended for use in autoimmune/inflammatory

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diseases at the present time, reason for optimism exists, and additional studies in these conditions should be performed.
FUTURE DEVELOPMENTS

In the next few years, we are likely to see continued evolution of SCIG therapy in the United States. Multiple IgG products are already marketed for SC use in Europe. Clinical trials are now underway in the United States using a next generation 16% solution and with two 10% IgG products currently marketed for IV use. In addition, one manufacturer already has a 20% IgG solution in clinical trials for SC treatment in PIDD, and another has published a method for generating and reconstituting 20% IgG solutions that are easily given through 28-gauge needles.56 Clinical trials of that type of preparation have not yet been initiated. It is likely that the availability of 20% solutions of IgG for SC use will provide further impetus for the use of this route to deliver high-dose IgG for autoimmune and inflammatory diseases. The availability of 20% solutions may also provide advantages for some patients using conventional doses of IgG for PIDD, because less volume will be needed to administer the same amount of IgG. However, studies that show that high-concentration products are tolerated as well as the alternatives must be completed before they come in clinical practice. Another approach to giving larger volumes of IgG SC is the injection of recombinant hyaluronidase to loosen the SC tissues by temporarily breaking down hyaluronic acid in the extracellular matrix of adipose and connective tissue. Apparently, the matrix is repaired rapidly, so the tissues are not changed permanently. Recombinant and other forms of hyaluronidase have been in clinical use in humans for some time for various indications, including enhancing the effects of local anesthetics, facilitating hydration by clysis, and in ophthalmic and plastic surgery.57 A recent study has shown that intradermal injections of a formulation of a recombinant human hyaluronidase was free from allergic reactions in 100 normal subjects.58 Preliminary reports suggest that an SC injection of hyaluronidase just before an infusion of IgG into the same site allows SC delivery of volumes of 10% IgG similar to those used for monthly IV treatment of PIDD patients in the same time that would be required for IV administration.59 Obviously, the ability to infuse larger volumes faster by the SC route, without the need for multiple sites, would be a distinct advantage for many PIDD patients. However, the ability of the weekly SC infusions now used by many patients to raise the trough level and eliminate wear-off effects would not be expected if the whole monthly dose was given at one time. Results of currently ongoing studies are anxiously awaited, to assess the safety and tolerance of these regimens and to determine how hyaluronidase-facilitated SC infusions will affect the treatment of PIDD. The results of the current studies are also likely to lead to further studies of SCIG in autoimmune and inflammatory diseases.
SUMMARY

The efficacy of SC administration of antibodies followed by purified IgG was recognized and used by von Behring and Bruton. The availability of IgG preparations that could be administered safely by the IV route was a long-sought goal that was finally achieved in the early to mid-1980s. IVIG revolutionized the treatment of PIDD and led to the discovery of the therapeutic value of high-dose IgG in autoimmune and inflammatory diseases not associated with PIDD. Improved therapy has improved outcomes and expectations, and most PIDD patients can lead fully active and productive lives. Administration of IgG by the SC route is effective and safe, overcomes obstacles

Subcutaneous Administration of IgG

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to the use of IVIG in some patients, and provides important quality-of-life advantages to others. The coming years will see increased use of SCIG in PIDD, which will be facilitated by advances leading to higher-concentration IgG products and easier delivery. Additional clinical research and the effects of these advances are likely to lead to increased use of SCIG in autoimmune and inflammatory diseases, in addition to more widespread use in PIDD.
REFERENCES

1. von Behring E. Serum therapy in therapeutics and medical science. Nobel Lecture 1901. Available at: www.nobelprize.org. Accessed January 30, 2008. 2. Berger M, Cupps TR, Fauci AS. Immunoglobulin replacement by slow subcutaneous infusion. Ann Intern Med 1980;98:556. 3. Roord JJ, Van der Meer JW, Kuis M, et al. Home treatment in patients with antibody deficiency by slow subcutaneous infusion of gammaglobulin. Lancet 1982;I:68990. 4. Ugazio AG, Duse M. Re R subcutaneous infusions of gammaglobulin in management of agammaglobulinemia. Lancet 1982;I:226. 5. Berger M, Cupps TR, Fauci AS. High dose immunoglobulin replacement therapy during pregnancy. J Am Med Assoc 1982;247:28245. 6. Welch MJ, Steihm ER. Slow subcutaneous immunoglobulin therapy in a patient with reactions to IM immunoglobulin. J Clin Immunol 1983;3:2856. 7. Chapel HM, Spickett GP, Ericson D, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 2000;20:94100. 8. Pac M, Bernakowska E. Polish experience with immunoglobulin replacement treatment by subcutaneous infusion. Central European Journal of Immunology 2005;30:7882. 9. Gardulf A, Hammarstrom L, Smith CIE. Home treatment of hypogammaglobulinemia with subcutaneous gammaglobulin by rapid infusion. Lancet 1991;338: 1626. 10. Kittner JM, Grimbacher B, Wulff W, et al. Patients attitude to subcutaneous immunoglobulin substitution as home therapy. J Clin Immunol 2006;26(4):4005. 11. Desai SH, Chouksey A, Poll J, et al. Comparison of efficacy and tolerability of equal doses of gamunex given IV or SC: a pilot study. J Allergy Clin Immunol 2008: submitted for publication. 12. Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol 2006;26:26573. 13. Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies - a prospective, multi-national study. J Clin Immunol 2008;26:17785. 14. Pharmacokinetics in Vivaglobin, summary of basis for approval. Available at: www.fda.gov/cber/sba/vivaglobin010906s.pdf. Accessed July 5, 08. 15. Pamarthi M, Taylor G, Scuderi P, et al. Subcutaneous availability of Gamunex in Rabbits. J Allergy Clin Immunol 2007;119:s16. 16. US Food and Drug Administration. Guidance for industry: safety, efficacy, and pharmacokinetic studies to support marketing of immune globulin intravenous (human) as replacement therapy for primary humoral immunodeficiency. Available at: http://www.fda.gov/cber/gdlns/igivimmuno.htm. Accessed January 7, 2008.

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17. Aebersold P. Intravenous immunoglobulins in the 21st century: progress and challenges in efficacy, safety and paths to licensure. FDA workshop 4/13/05. Available at: www.fda.gov/cber/minutes/igiv041305t.htm. Accessed July 5, 2008. 18. Emea. Note for guidance on the investigation of human normal immunoglobulin for subcutaneous and intramuscular use. CPMP/BPWG/283/00. 2002. Available at: www.emea.europa.eu/pdfs/human/bpwg/028300.en.pdf. Accessed July 5, 2008. 19. Waldmann TA, Strober W, Blaese RM. Metabolism of immunoglobulins. Progress in Immunology 1972;891903. 20. Mankarious S, Lee M, Fischer S, et al. The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin. J Lab Clin Med 1988;112(5):63440. 21. Vivaglobin prescribing information. CSL-Behring. King of Prussia, PA. 22. Waniewski J, Gardulf A, Hammarstrom L. Bioavailability of gamma-globulin after subcutaneous infusions in patients with common variable immunodeficiency. J Clin Immunol 1994;14:907. 23. Sewell WAC, editor. Subcutaneous immunoglobulin therapy medical education programme. Oxfordshire (UK): Watermeadow Medical plc; 2006. 24. Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol 2004;112:17. 25. Ballow M. Safety of IGIV therapy and infusion-related adverse events. Immunol Res 2007;38(13):12232. 26. Gardulf A, Anderson V, Bjorkander J, et al. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 1995;345:3659. 27. Gardulf A, Bjorvell H, Gustafson R, et al. The life situations of patients with primary antibody deficiency untreated or treated with subcutaneous gammaglobulin infusions. Clin Exp Immunol 1993;92:2004. 28. Radinsky S, Bonagura V. Subcutaneous immunoglobulin infusion as an alternative to intravenous immunoglobulin. J Allergy Clin Immunol 2003;112:6303. 29. Immune Deficiency Foundation. Treatment experiences and preferences of patients with primary immune deficiency diseases: first national survey. 2003. Available at: www.primaryimmune.org/publications/surveys/Treatment_Experiences_ and_preferences_(2003). Accessed July 5, 2008. 30. Gardulf A, Nicolay U, Math D, et al. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol 2004;114:93642. 31. Nicolay U, Kiessling P, Berger M, et al. Health-related quality of life and treatment satisfaction in North American patients with primary immunedeficiency diseases receiving subcutaneous IgG self-infusions at home. J Clin Immunol 2006;26:6572. 32. Gardulf A, Bjorvell H, Andersen V, et al. Lifelong treatment with gammaglobulin for primary antibody deficiencies: the patients experiences of subcutaneous self-infusions and home therapy. J Adv Nurs 1995;21:91727. 33. Gardulf A, Andersson E, Lindqvist M, et al. Rapid subcutaneous IgG replacement therapy at home for pregnant immunodeficient women. J Clin Immunol 2001;21: 1504. 34. Arora R, Newton TC, Nelson MR. Subcutaneous Ig therapy in an 11-year-old patient with common variable immunodeficiency and von Willebrands disease. Ann Allergy asthma Immunol 2007;99:36770.

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35. Sundin U, Neva S, Hammarstrom L. Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy. Clin Exp Immunol 1998;112:3416. 36. Ho C, Membe S, Cimon K, et al. An overview of subcutaneous vs. intravenous immunoglobulin for primary immunodeficiencies: systematic review and economic analysis [technology overview #36]. Ottawa (Canada): Canadian Agency for Drugs and Technologies in Health; 2008. Available at: http://www.cadth.ca/index.php/en/ publication/785. Accessed August 26, 2008. 37. Hogy B, Keinecke HO, Borte M. Pharmacoeconomic evaluation of immunoglobulin treatment in patients with antibody deficiencies from the perspective of the German statutory health insurance. Eur J Health Econ 2005;6:249 [with Erratum in 6:243, 2005]. 38. Gardulf A, Bjorvell H, Gustafson R, et al. Safety of rapid subcutaneous gammaglobulin infusions in patients with primary antibody deficiency. Immunodeficiency 1993;4:814. 39. Gaspar J, Gerritsen B, Jones A. Immunoglobulin replacement treatment by rapid subcutaneous infusion. Arch Dis Child 1998;79:4851. 40. Hansen S, Gustafson R, Smith CIE, et al. Express subcutaneous IgG infusions: decreased time of delivery with maintained safety. Clin Immunol 2002;104: 23741. 41. Berger M, Duff K, Poll J, et al. Immunoglobulin replacement therapy by the subcutaneous route using preparations licensed in the US for administration by other routes. In: Dalakis M, Spath PJ, editors. Intravenous immunoglobulins in the third millenium. New York: Parthenon; 2004. p. 7780. 42. Chouksey A, Duff K, Wasserbauer N, et al. Subcutaneous IgG replacement therapy with preparations currently available in the US for IV or IM use: reasons and regimens. Allergy Asthma Clin Immunol 2005;1:12030. 43. Guidelines for subcutaneous IgG therapy. Available at: www.ukpin.org.uk/ guidelines3.-01-Administration-SCIG.pdf. Accessed July 5, 2008. 44. Berger M, Duff K, Beal C. Information for patients: pumps and needles used for subcutaneous IgG. Available at: http://www.rainbowbabies.org/subcu. Accessed January 7, 2008. 45. Gustafson R, Gardulf A, Hansen S, et al. Rapid subcutaneous immunoglobulin administration every second week: results in high and stable serum IgG levels in patients with primary antibody deficiencies. Clin Exp Immunol 2008;152:2749. 46. CSL-Behring, King of Prussia, PA. Vivaglobin patient brochure. Available at: www. vivaglobin.com/PDF/patient_brochure.pdf. Accessed July 5, 2008. 47. Baxter, Vienna, Austria. Subcuvia Patient Brochure. Available at: www. immunediseaseeurope.com/ideu/pdfs/10020_subcuvia_patient_bro_print.pdf. Accessed July 5, 2008. 48. NIH Clinical center nurses: patient information publications. giving a subcutaneous injection. Available at: www.cc.nih.gov/ccc/patient_education/pepubs/subq. pdf. Accessed January 7, 2008. 49. Berger M, Duff K. The story of subcutaneous IgG, and other materials. Available at: www.rainbowbabies.org/sbcu. Accessed July 5, 2008. 50. Berger M. Subcutaneous IgG therapy in immune deficiency diseases. Immune Deficiency Foundation Clinical Focus issue 13, 2008. Available at: www. primaryimmune.org/publications/clinic_focus/cc_feb08.pdf. Accessed July 5, 2008.

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51. Stiehm ER, Casillas AM, Finkelstein JZ, et al. Slow subcutaneous human IGIV in the treatment of antibody immunodeficiency: use of an old method with a new product. J Allergy Clin Immunol 1998;101:8489. 52. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Tansfus Med Rev 2003;17:24154. 53. Dalakas MC. Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of autoimmune neurologic diseases. Neurology 1998;51(Suppl 5):S28. 54. Lee DH, Linker RA, Paulus W, et al. Subcutaneous immunoglobulin infusion: a new therapeutic option in chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 2008;37:4069. 55. Koller H, Schroeter M, Feischen H, et al. Subcutaneous self-infusions of immunoglbulins as a potential therapeutic regimen in immune-mediated neuropathies. J Neurol 2006;253:15056. 56. Dani B, Platz R, Tzannis ST. High concentration formulation feasibility of human IgG for subcutaneous administration. J Pharm Sci 2007;96:150417. 57. Frost GI. Recombinant human hyaluronidase (rHUPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opin Drug Deliv 2007;4: 42740. 58. Yocum RC, Kennard D, Heiner LS. Assessment and implication of the allergic sensitivity to a single dose of recombinant human hyaluronidase injection: a double blind, placebo-controlled clinical trial. J Infus Nurs 2007;30:2939.

Pharmacokinetic s of I mmunoglobulin Administere d via I ntravenous or Sub cut a ne ous Routes

Francisco A. Bonilla, MD, PhDa,b,*
KEYWORDS  Immunoglobulin  Intravenous  Pharmacokinetics  Subcutaneous

Polyclonal human immunoglobulin G (IgG) therapy is applied in many disease states, including primary and secondary immunodeficiencies, and a wide variety of infectious, autoimmune, and inflammatory disorders.1 The practical use of IgG therapy derives in large measure from its peculiar pharmacokinetic properties, which are reviewed in this article. In particular, IgG circulates intact in serum for a period of time that is several fold longer than almost any other class of serum protein. This permits IgG to be administered intermittently and relatively infrequently (intervals measured in weeks) with persistent effectiveness between successive administrations. Although therapeutic replacement of other Ig classes (IgA and IgM) has been studied, we focus our discussion entirely on IgG, because it is the only isotype available for routine clinical use. IgG may be administered by intramuscular (IM), subcutaneous (SC), or intravenous (IV) routes; IgG administered by each of these routes is abbreviated IMIG, SCIG, and IVIG, respectively. IM injection is no longer considered appropriate for routine replacement therapy in light of the superior ease of administration and efficacy via the IV and SC routes. Polyvalent IgG formulated for IM administration may be given by the SC route with good results.2 IM injection is still appropriate for administration of specific Ig for infection prophylaxis (eg, tetanus, rabies, hepatitis B, varicella) because the effectiveness of SC administration of any of these products has not been determined.

Division of Immunology, Childrens Hospital Boston, Fegan Building, 6th Floor, 300 Longwood Avenue, Boston, MA 02115, USA b Department of Pediatrics, 25 Shattuck Street, Harvard Medical School, Boston, MA 02115, USA * Division of Immunology, Childrens Hospital Boston, Fegan Building, 6th Floor, 300 Longwood Avenue, Boston, MA 02115. E-mail address: francisco.bonilla@childrens.harvard.edu Immunol Allergy Clin N Am 28 (2008) 803819 doi:10.1016/j.iac.2008.06.006 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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This article focuses mainly on pharmacokinetic studies of polyclonal human IgG via IV and SC routes administered for replacement and infection prophylaxis in primary and secondary immunodeficiency states.
PHYSIOLOGY OF IMMUNOGLOBULINS

Important studies of immunoglobulin (Ig) synthesis and catabolism in humans in vivo were conducted in the 1960s. In particular, the work of Waldmann and colleagues3,4 established the fundamental behaviors of various Ig isotypes under a variety of physiologic and pathologic conditions. To determine the rate of disappearance of Ig by protein catabolism, these authors injected volunteers with small amounts of radioactive Ig of various isotypes and examined the rate of decline of serum radioactivity. Table 1 summarizes some of these data. These authors calculated the total body content of IgG to be 1.1 g/kg with 45% in the intravascular compartment. These studies quickly determined that IgG catabolism has important differences in comparison to other isotypes. The major contrast is that catabolism of IgG is not only slower than all other Ig classes, but it is also proportional to its serum concentration. The fractional catabolic rate of IgG increases as the serum concentration rises and vice versa (Fig. 1), which is not true of any other Ig class. Researchers further observed that this feature depended entirely on the Fc portion of IgG, because any IgG fragments that did not contain Fc were rapidly catabolized (see Table 1), and the rate was independent of their concentrations. At the time, researchers hypothesized that a saturable protection receptor system for IgG Fc could explain these findings.5 Approximately 30 years later, researchers established that the principal mechanism of regulation of serum IgG level involves the neonatal Fc receptor (FcRn).6 This receptor derives its name from its earliest known functiontransport of IgG from the newborn proximal small intestine into the circulation.7 Later, it was found to transport IgG from the maternal bloodstream into the fetus during gestation.8 This receptor is also expressed on vascular endothelium, where it acts to increase IgG half-life. (The receptor also binds serum albumin and increases its half-life.) More recently, FcRn has been found in various organs and tissues and may play a wider role in IgG physiology and humoral immunity than previously appreciated.9
Table 1 Serum half-lives of immunoglobulins in healthy adults Ig IgGa IgG1b IgG2b IgG3b IgG4b Fca Faba L chaina Half-Life (d) 23.0 21.0 21.0 7.1 21.0 10-20 0.18 0.14 FCR 6.7 Ig IgAa IgMa IgDa IgEa Half-Life (d) 5.8 5.1 2.8 2.5 FCR 25.0 18.0 37.0 89.0

Abbreviation: FCR, fractional catabolic rate (percent of intravascular pool per day). a Data from Waldmann TA, Strober W, Blaese RM. Variations in the metabolism of immunoglobulins measured by turnover rates. In: Merler E, editor. Immunoglobulins. Washington, DC: National Academy of Sciences; 1970. p. 3351. b Data from Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin Invest 1970;49:67380.

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100 90 80 70 60 50 40 30 20 10 0 0 20 40 60 80

IgG survival t1/2 (days)

Fig.1. Concentration dependence of IgG catabolism. (From Waldmann TA, Strober W, Blaese RM. Variations in the metabolism of immunoglobulins measured by turnover rates. In: Merler E, editor. Immunoglobulins. Washington, DC: National Academy of Sciences; 1970. p. 38; with permission.)

FcRn is composed of an a chain homologous to human leukocyte antigen class I molecules that also must pair with b2 microglobulin for surface expression and function. The receptor does not bind short peptides, however, and the gene encoding the alpha chain is not located in the human leukocyte antigen gene complex on chromosome 6 (the FCGRT gene encoding FcRn is on chromosome 19q13.3). The mechanism of the concentration dependence of IgG catabolism mediated by FcRn is illustrated in Fig. 2. Promoter polymorphisms of the FCGRT gene lead to variations in levels of FcRn expression,10 which might underlie some of the variability of IgG levels between individuals, although this has not been reported. In 1968, Waldmann and colleagues11 described two siblings with familial idiopathic hypercatabolic hypoproteinemia who had low serum levels of IgG and albumin. In these individuals, the rate of catabolism of IgG was fivefold greater than normals, and serum IgG levels were 130 to 440 mg/dL. Almost 40 years later, these individuals were found to harbor mutations of b2 microglobulin, which reduced expression of FcRn by more than 80%.12 These siblings are the only two reported patients with this entity (OMIM #241600). Understanding the particular pharmacokinetic properties of IgG Fc together with recombinant DNA technology has led to the development of an entire class of biologic therapeutic agents, the IgG fusion proteins. These agents have a non-Ig therapeutic component, linked to an IgG Fc fragment, to borrow its ability to confer a prolonged time in the circulation, enhancing its bioavailability and therapeutic effect.13
IMMUNOGLOBULIN G REPLACEMENT THERAPY

IgG replacement therapy is indicated for primary or secondary immunodeficiencies with hypogammaglobulinemia or impaired specific antibody formation.1 Purified

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A
Low IgG
IgG Endocytosis Recycle to surface

Membrane

FcRn Degradation in lysosome

B
High IgG

Fig. 2. FcRn is expressed on the surface of vascular endothelium (and other cell types that may mediate this function, such as monocyte derived cells). Plasma is endocytosed, and acidification favors IgG binding to FcRn; an equilibrium is reached with some fraction of IgG bound to FcRn and some free within the endosome. (A) When IgG is relatively low, a small amount remains unbound after endocytosis and is sent to a degradative pathway, whereas FcRn with bound IgG is shuttled back to the cell surface. Physiologic pH promotes dissociation, and intact IgG is released into the circulation again. In this example, 20% of the IgG that was taken up was degraded. (B) When the concentration of IgG is relatively high, FcRn becomes saturated, and a greater proportion of circulating IgG remains unbound and is ultimately broken down. In this example, 50% of the IgG taken up was eliminated.

human IgG preparations have been formulated specifically for IM, SC, and IV administration. Preparations suitable for IM or IV use may be given SC;2 however, preparations intended for IM or SC use may not be given IV because of content of IgG aggregates that may lead to systemic reactions. Dose regimens have been determined empirically in clinical trials to determine the preinfusion (trough) IgG levels that are associated with adequate clinical efficacy.1 Several of these studies are also mentioned here. The minimum trough level consistent with effective protection in agammaglobulinemic individuals is approximately 500 mg/dL. There is measurable improvement in outcomes (reduced rate of infections) when trough levels are driven as high as 900 to 1000 mg/dL, however. Standard dose regimens for IgG replacement are shown in Table 2.
PHARMACOKINETICS OF INTRAVENOUS IMMUNOGLOBULIN

After administration of relatively large amounts of IVIG (0.12 g/kg body mass), the IgG concentration in serum immediately rises, falls rapidly in the first 1 to 7 days, and then falls more slowly thereafter. The initial rapid fall is associated with passage of IgG out

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Table 2 Common dosing regimens for immunoglobulin G replacement therapy via intramuscular, intravenous, and subcutaneous routes Dose IMIG IVIG SCIG 0.025 g/kg 0.30.8 g/kg 0.050.2 g/kg Interval weekly 24 wk 0.52 wk Concentration of Infused IgG (%) 1616.5 512 1016.5

Low doses are given at shorter intervals; higher doses are given at longer intervals.

of the vasculature into lymph and extracellular fluid compartments. The subsequent decline is mainly caused by catabolism while IgG in lymph and tissues slowly diffuses back into the circulation. Many studies of healthy individuals model the IgG concentration using two compartments: the vascular and extravascular spaces with an equilibrium between the two and with the vascular space being the point of entry and exit (Fig. 3A). The IgG concentration decay curve may be subdivided into two phases commonly designated as a (early) and b (late) (Fig. 3B). Although this mathematical description is appropriate in many circumstances, it is not universally applied in studies of IVIG pharmacokinetics. Many studies use alternative pharmacologic models (eg, noncompartmental, single compartment).14 Simpler models used to describe longer infusion intervals (weeks) are more likely to deviate from the observed decay curve in the early phase, as opposed to the late phase. The importance of this deviation for practice is unclear, however. With respect to replacement therapy, primary emphasis

IVIG

Synthesis SCIG

B
Serum IgG concentration

Early () phase

Late () phase

Intravascular compartment

Extravascular compartment(s)

Trough IgG level

IVIG

IVIG

14

21

28

Time (days)
Catabolism Loss

Fig. 3. Two-compartment model of IgG pharmacokinetics. (A) IgG is in equilibrium between the vascular space and extravascular areas. IgG is synthesized in the bone marrow and diffuses into the lymph and then to the blood. SCIG is absorbed from subcutaneous tissues. IVIG enters the vascular space directly. IgG is catabolized in vascular endothelium (and possibly other areas). IgG also may be lost from the vascular space by various mechanisms (eg, protein loss in the intestines or urinary tract). (B) Serum IgG concentration over time during IVIG replacement therapy. With IV administration, IgG enters the vascular compartment in high concentration, redistributes rapidly into tissue compartments, and then is more slowly catabolized. The early redistribution phase is sometimes called the a phase, and the later slow decline is the b phase.

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is placed on the trough (immediate preinfusion) IgG level. Many studiesparticularly most studies conducted by IVIG manufacturersderive an empiric serum or plasma decay half-life (t1/2) as the principal descriptor of the expected rate of disappearance of the infused IgG.
Primary Immunodeficiency

Table 3 shows the serum half-lives of several of the IVIG products currently in use. These data were derived mainly from clinical trials of IVIG replacement in patients with primary immunodeficiency.1522 Most patients in these trials had either X-linked agammaglobulinemia or common variable immunodeficiency. The ranges of doses administered in these trials vary widely from approximately 0.3 to 0.6 g/kg, and the dose intervals vary. In some cases, dose intervals of 3 or 4 weeks are analyzed
Table 3 Elimination half-lives of some intravenous immunoglobulin G products t1/2 (d) Mean SD 38 15 r 1672 Flebogamma 5% Flebogamma 5% DIF 29.9 9.5b 30 9 r 1941 32 5 r 2539 GAMMAGARD 35d 10% 95% CI (3142) Gamunex Octagam 34.9f 34.7
f a

Product Carimune NF

AUC (d*mg/dL) Mean SD 27,100 9400 29,448 9319 31,159 6572 r 20,45840,104 32,894 3886 27,65041,814 29,139e (95% CI 27, 49430,490) 16,010 3460 r 10,38022,860 32,820 6260 r 28,58040,010 36,390 5950 r 19,68044,340

AUC Time Dose; Mean Interval 21 d 28 dc 28 d 28 dc 28 d 28 d 21 d 21 d 28 d 0.30.6 g/kg; 3 wk 0.30.6 g/kg; 4 wk 0.30.6 g/kg; 3 wk 0.30.6 g/kg; 4 wk

Reference
19

0.30.8 g/kg; 3 or 4 wk 16 10 8 12

18

44.6 13.4 32,694 9848

11
17

20

0.30.6 g/kg; 3 or 4 wk 57

16

0.20.6 g/kg; 3 or 4 wk 17 0.30.6 g/kg; 3 or 4 wk 46 0.20.42 g/kg; 3 wk 0.20.888 g/kg; 3 wk 0.20.888 g/kg; 4 wk 17 3

0.30.5 g/kg; 3 or 4 wk 14
21

41 17 r 2384 36 11 r 1856

15

22

Privigen

28 6 r 2233 45 19 r 2197

22
19

Sandoglobulin 45 19 r 1588

28,400 11,700 21 d

0.30.8 g/kg; 3 or 4 wk 15

Abbreviation: AUC, area under the curve. a Range. b Mean SE. c Patients on the 3-week interval regimen had one sampling period of 4 weeks for pharmacoki netic analysis. d Median. e Pharmacokinetic analysis was over 28 days; the reported AUC corresponds to 21 days after infusion. f Geometric least-square mean; two separate analyses were reported.

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together; in others, they are analyzed separately. For cases in which they are analyzed separately, it is evident that the shorter dose interval (higher cumulative IgG dose over time) tends to be associated with a shorter half-life. It is also clear that there is tremendous individual variation in rates of decay in each study. Sources of variability include different dose regimens, time of sampling, variability in IgG measurement, amount and rate of endogenous IgG production, and actual individual variation in rates of IgG catabolism. The variability in measured IgG decay rates is so great that it is unlikely that statistical differences could be established between regimens with one product or between products. Two studies have compared pharmacokinetic parameters for two different IVIG preparations.16,19 Both studies concluded that the products were pharmacologically equivalent (no statistical difference in measured parameters). Replacement dose regimens of IVIG have evolved toward ever higher amounts over the last few decades. Initial regimens were based on doses that had been administered IM, and immunodeficient patients were often given a cumulative monthy replacement dose of 0.1 g/kg (four weekly injections of 0.25 g/kg). One early study compared pharmacokinetics of IgG in 16 patients who had primary immunodeficiency diseases (PID) receiving low dose (0.1 g/kg monthly) with high dose (average 0.35 g/kg monthly, titrated to give a trough IgG level of 450 mg/dL).23 The half-lives ranged from 22 to 96 days (mean, 43 days) at the lower doses and 20 to 59 days (mean, 33 days) at the higher doses. (This product is no longer available and is not included in Table 3.) There was no statistical difference between these values, however. The authors also suspected that some level of endogenous IgG production in some patients was affecting (prolonging) the half-life determinations. In a more recent study, 41 patients were compared with respect to two different dose regimens.24 In this study, the low dose regimens were 0.3 g/kg and 0.4 g/kg every 4 weeks in adults or children, respectively; the high dose regimens were 0.6 g/kg and 0.8 g/kg every 4 weeks in adults and children, respectively. The authors did not attempt any pharmacokinetic study other than monitoring the trough IgG levels, which rose by an average of 45% (from 640 up to 940 mg/dL). This increase was associated with significant improvements in patients clinical courses. Most authors emphasize that controlling the trough IgG level, together with monitoring the clinical course, is most important for determining the appropriate replacement regimen for individual patients. A few recent studies measured half-lives of IgG subclasses after IV administration of a single product to patients with PID.15,18 These data are summarized in Table 4. The total IgG half-life is dominated by the contributions of IgG1 and IgG2, which have roughly similar half-lives within studies, and together accounted for 90% to 95% of the infused IgG. One study found that IgG3 and IgG4 had relatively shorter half-lives in comparison to IgG1 and IgG2.15 Another study found that IgG3 and IgG4 had similar or longer half-lives in comparison to IgG1 and IgG2, however.18 This study also compared pharmacokinetic parameters between patients receiving infusions either every 3 weeks or every 4 weeks and found a trend toward longer half-lives associated with patients on the 4-week regimen. In these studies, the half-life of IgG3 did not seem to be as short as indicated from radioactive tracer studies (see previous discussion), whereas the half-life of IgG4 seemed to be either shorter than had been determined by tracer methods15 or possibly much longer.18 The differences between assessing pharmacokinetics via catabolism of trace amounts of radiolabeled IgG in healthy individuals in contrast to serum level decay during replacement therapy in immunodeficient patients are so great as to severely limit the usefulness of the comparison. Differences between physicochemical alterations of IgG subclasses during radioiodination or purification of IgG

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Table 4 Half-lives of IgG subclasses in intravenous immunoglobulin G replacement therapy for primary immunodeficiency disease Class/Subclass IgG1 Half-Life (d, Range) 36.3 9.2a, r 2351.5 26.4 8.4b 40.6 12.2c IgG2 37.1 13.9, 22.962.5a 33.8 10.7b 53.8 16.2 IgG3
c a

AUC (d*mg/dL, Range) 10,050 2470, 571015,040 19,193 6074 21,657 6523 2990 850, 18004360 10,370 3282 10,776 3246 664 333, 3591739 995 315 1434 432
a

AUC Time (d) 21 28 28 21 28 28 21 28 28 21 28 28

n 17 10 11 17 10 11 17 10 11 17 10 11

Reference
15

18 18 15

18 18 15

28.6 10.4, 1350.2 33.6 10.6b 49.9 15.0

c

18 18 15 18 18

IgG4

15.6 14.5, 7.124.7 42.2 13.4 75.9 22.9

b c

39 21, 22109 489 155 648 195

Abbreviation: AUC, area under the curve. a Data are mean SD. See Table 3 for total IgG data. b Data are mean SE, 3-week dose regimen. See Table 3 for total IgG data. c Data are mean SE, 4-week dose regimen. See Table 3 for total IgG data.

for IV administration also may affect the pharmacokinetics in vivo. As expected, the areas under the curve for each subclass correlate most closely with the relative proportions of each IgG subclass in the IVIG preparation. Some researchers consider that measurement of elimination half-lives by measuring specific antibody levels may be more accurate than measurement of total IgG. The theoretic argument is that there is likely to be less interference via the production of endogenous specific antibody. One study also measured tetanus specific antibody after IVIG infusion.23 The authors found mean half-lives ranging from 27 to 36 days in the higher dose phases of their study (range of all patients 1649 days), overall comparable to rates determined by total IgG (Table 5). Another study in patients who have PID determined IgG decay rates using specific antibody levels (see Table 5).25 This study also found comparable values of decay rates (mean SD) for total IgG, 25.9 18.1; IgG1 29.7 18.1; IgG2, 26.9 11; and IgG3 15.7 5.2 (the value of IgG3 tends to be lower than the others in this study; the product is no longer in use and is not included in Tables 3 and 4).
Burn Patients

In some cases, primary or secondary abnormalities of protein catabolism may lead to decreased serum half-life of IgG. Deficiency of b2 microglobulin has been mentioned as one primary cause of increased IgG catabolism (see discussion of bone marrow transplantation in later section). Burn trauma may lead to a secondary increase in IgG catabolism by an unknown mechanism. In one study of nine patients with large burns (30%50% body surface area) who received 0.5 g/kg IVIG once or twice weekly, the half-lives for early (days 01) and late (days 14) decay were 4.4 and 12.4 days, respectively.26 The early period in this study was dominated by redistribution, but

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Table 5 IgG half-lives determined by specific antibody levels Organism/Antibody Adults/children with PID Tetanus toxoid (3-wk dose interval) Salmonella minnesota lipopolysaccharide Streptococcus pneumoniae types 1, 3, 6A, 8, 14, 19F Cytomegalovirus Infants Respiratory syncytial virus 0.50.75 g/kg monthly Neonates Streptococcus pyogenes group B type III Escherichia coli Cytomegalovirus
a

Mean Half-Life (d) 2736 r 1649, n 5 15 27.2 12.4 37.6 9.8 29.5 5.9 2128 n 5 23 3.4 6.7 4.7

Reference
23

25 25 25

38

28a 28a 28a

Also see Table 6.

this was also probably occurring to some extent even during the late period. In both phases there may be initial skin loss (although this disappears as the burn heals) and changes in IgG catabolism induced by systemic effects of the burn trauma. It is also possible that the extravascular pool is increased by accumulation of fluid in burned skin. Another study looked at 20 patients with large burns (12%94% surface area) who received 0.5 g/kg IVIG weekly.27 The authors found a half-life of 2 days in the first week after injury and a half-life of 6.4 days in the second and third weeks after injury. This study performed pharmacokinetic analysis over a 96-hour period, still dominated by IgG redistribution. Although these data suggested at least the possibility of increased catabolism as a contributing factor, it is not possible to compare these results directly with results that measure half-lives in patients receiving replacement every 3 to 4 weeks.
Neonates

Several studies examined IVIG therapy for prophylaxis and treatment of neonatal sepsis.2835 Meta-analyses concluded that adjunct therapy with IVIG reduces mortality in neonatal sepsis36 and is effective as a prophylactic regimen.37 Some of these studies have included pharmacokinetic analyses. These data are summarized in Table 6. Comparison between these studies is difficult because of the different designs (mainly the sizes of patients and dose regimens), different pharmacokinetic models, and sampling periods. The earliest studies suggested shorter half-lives than those found in subsequent trials. Where included in these reports, data also showed large individual variations. With the exception of the first study in Table 6, longer sampling periods seem to be associated with longer half-lives, which suggests that this leads to more accurate determination or a systematic bias. Authors emphasize the importance of monitoring trough IgG levels during therapy. For all of the same methodologic reasons noted previously, it is difficult to compare these studies to those conducted over longer terms in older children and adults. Broadly speaking, studies in neonates indicate somewhat shorter IgG half-lives by

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Table 6 Intravenous immunoglobulin G half-lives in neonates Birth Weight (g) 21403,550 6403340 7501000 7501500 Dose (g/kg), Interval 0.5, single infusion 0.5, weekly 0.5, single dose 0.75, single dose 0.5, single infusion 0.75, single infusion 1.0, single infusion < 10002000 > 1500 < 10001500 5002000
a b c d

Sample Period (d) 42 7 28 28 28 28 28 214 days 10 weeks 42 14 56

Half-Life, d (Range) 11.3a 0.6, n 5 5 10.8 , n 5 134 22.8 5.9 (13.530.1), n 5 10 22.6 5.6 (11.930.1), n 5 10 22.1b (18.134.7), n 5 3 28.7 (19.641.5), n 5 4 19.6b (15.826.3), n 5 6 (1632), n 5 46 33 , n 5 46 24.2a 7.2, n 5 15 18.1 (95% CId 15.520.6), n 5 35 28.9 19.6, n 5 372
a c b a a a

Reference
33 28 32

31

30

0.51.3, 214 d None (placebo) 0.251.0, single dose 0.75, 2 wk 0.5, single infusion

34 29 35

Mean, or mean SD. Harmonic mean. Represents maternal IgG. 95% confidence interval.

comparison. One study measured the decline in endogenous (maternal-derived) IgG in newborns (see Table 6).30 They determined an elimination half-life of 33 days, comparable to studies of patients who have PID (see Table 3). The authors did not account for endogenous IgG production, however, which could prolong the measured half-life. The IgG levels in these patients also were much lower than in those receiving ongoing replacement therapy, leading to a lower catabolic rate (see previous discussion). At least one study examined IgG elimination by measuring specific antibody in neonates.28 This group found the shortest measured half-lives by this method, ranging from 3 to 7 days (see Table 5). The reason for such short half-lives is unclear; this study did sample over a short period that was likely dominated by the redistribution phase, which may have affected the data based on total IgG as well. Another study examined the kinetics of antibody to respiratory syncytial virus in infants and young children receiving infusions of IVIG with high titer respiratory syncytial virus antibody (see Table 5).38 Their data showed half-lives comparable to those determined by tracer studies in healthy individuals and somewhat lower than determined by total IgG or other antibodies in older child and adult patients who have PID.
Bone Marrow Transplantation

IVIG has been used as infection prophylaxis for patients undergoing bone marrow transplantation, and this is one of the US Food and Drug Administrationapproved indications for IVIG therapy.1 Several studies have examined kinetics of IVIG in bone marrow transplantation recipients as determined by total IgG levels and cytomegalovirus (CMV)-specific antibodies (Table 7).3943 These studies all tend to show short IgG half-lives. Comparison among these studies is challenging for the reasons noted previously in attempting to compare studies in patients who have PID or in neonates. They are further complicated by variations in the timing of the replacement dosing with respect to the initiation of a myeloablation regimen and the level of

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Table 7 IVIG elimination in bone marrow transplantation and malignancy Measure Total IgG Total IgG Total IgG CMV antibody CMV antibody CMV antibody Total IgG Total IgG Dose (g/kg), Interval 0.5, 12 wk 0.250.5 weekly 0.5, weekly 0.5, weekly 0.2, 14 d 0.5, single dose 0.4, 3 wk 0.1, 3 wk 0.4, 3 wk 0.8, 3 wk Pneumococcusd 0.1, 3 wk 0.4, 3 wk 0.8, 3 wk Multiple myeloma Total IgG 0.1, 3 wk 0.4, 3 wk 0.8, 3 wk Pneumococcusd 0.1, 3 wk 0.4, 3 wk 0.8, 3 wk
a

Sample Period (d) 714 7 7 7 14 14 21 21 21 21 21 21 21 21 21 21 21 21 21

Mean Half-Life, d 1.31.9a, n 5 41 6.2, n 5 31 5.0 6, n 5 9 2.925.5, n 5 27 1.32.8, n 5 18 3.512.5, n 5 9 39.1 9.6, n 5 9 r 24.956.5
c b

Reference
40 42 43 43 41 39

Bone marrow transplantation

Chronic lymphocytic leukemia

44

45

112.7c, n 5 10 49.7 , n 5 10 44.8c, n 5 10 59.5 48.3, n 5 10 55.3 16.8, n 5 10 49.7 9.1, n 5 10 215.6c, n 5 10 61.6 , n 5 10 42.7c, n 5 10 37.1 6.3, n 5 10 38.5 6.3, n 5 10 36.4 3.5, n 5 10
c

45

45

45

Where a range is shown in this manner, it represents the range of mean half-lives that were calculated in various subgroups of patients. Range of individual patient half-life determinations. c Median. d Twelve serotypes; data are aggregated across serotypes.
b

pre-existing antibody. All of the studies use short dosing intervals and sampling times and simple pharmacokinetic models. It is possible that these features again bias toward shorter elimination half-life calculations. There is great variability between patient subgroups or individual patients. In one study43 a large range of half-lives was observed as determined by CMV antibody, and in several cases it exceeded the half-life determined by total IgG level. There seemed to be an influence of initial CMV antibody because longer half-lives were found in patients with higher initial levels. The authors also speculated that their assumptions regarding stability of ongoing endogenous IgG production during the early study period may have led to a bias toward a shorter half-life determination based on total IgG level. Another study examined half-lives of IgG subclasses as determined by subclassspecific assays for CMV antibody in two patients.41 In those two patients the total IgG half-lives were 1.6 and 3.4 days. The CMV-specific antibody half-lives (days) were comparable as follows: IgG1, 1.0 and 2.5; IgG2, 1.0 and 3.0; IgG3, 1.5 and 3.4; IgG4, 0.7 and 2.5. As yet, there is no explanation for the apparent increased

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rate of disappearance of IgG from the circulation in patients who receive infusion after bone marrow transplantation.
Malignancy

A few studies of IgG kinetics in malignancy have been conducted (Table 7), including chronic lymphocytic leukemia and multiple myeloma.44,45 One study based on total IgG measurement in replacement therapy for chronic lymphocytic leukemia found results comparable to replacement for PID.44 Another study that included chronic lymphocytic leukemia and multiple myeloma found elimination half-lives considerably longer than any reported previously.45 The data did suggest that higher dose regimens led to shorter half-lives; however, the high IgG levels at baseline in patients with multiple myeloma appeared possibly to reflect not only increased IgG synthesis but also reduced catabolism. The prolonged half-lives were also reflected in measurements determined by levels of specific (antipneumococcal polysaccharide) antibodies, although the apparent increase was not as marked.
PHARMACOKINETICS OF SUBCUTANEOUS IMMUNOGLOBULIN

Ig administration via the SC route is fundamentally different from IV administration.2 The dose is absorbed slowly and redistributed slowly, whereas concentrationdependent catabolism is ongoing. It is impractical to administer SCIG by a dose regimen comparable to IVIG, because of the relatively limited amount that can be accommodated subcutaneously (approximately 530 mL per site, depending on size/body mass index), even when multiple sites are used. Although IVIG is usually administered every 3 to 4 weeks, SCIG is dosed weekly, or sometimes twice weekly; the amount of IgG administered over time is generally equivalent. Because the amount administered at each SCIG infusion is smaller and the interval is shorter, the fluctuations in IgG level that are characteristic of IVIG dosing are expected to be much smaller. One also would expect these fluctuations to be blunted by the relatively slow absorption of SCIG from the infusion sites (see Fig. 3A; Fig. 4A). Few formal pharmacokinetic studies of SCIG have been conducted. One early study compared IM and SC administration (eight patients each) of 125I-labeled anti-Rho Ig in tracer studies similar to those described for IV injection.46 The authors found IM injection to lead to somewhat more rapid uptake, with 70% of maximum plasma level reached after 1 day, and the maximum levelcorresponding to 40% of the injected doseoccurring after 2 to 4 days. With SC administration, 45% of the maximum plasma level was reached in 1 day, whereas the maximum levelcorresponding to 33% of the injected dosewas reached in 4 to 6 days. Regardless of the mode of administration, plasma levels in the first 24 hours varied erratically, reflecting possible discontinuous absorption followed by rapid dilution and early redistribution to other sites. The calculated uptake rates were 0.43 0.11 (mean SD, fraction per day) for IM injection and 0.22 0.025 for SC administration. The authors performed two separate studies and calculated elimination half-lives independently of IM or SC administration. In one study of seven patients they found t1/2 5 22 4 days; in another study (n not specified) they reported a range of t1/2 of 22 to 46 days, which was similar (not surprisingly) to results obtained after IV administration. In an early study of SCIG in 23 patients who had PID, a 16.5% concentration product formulated for IM use was infused SC at a dose of 0.1 g/kg weekly.47 The authors found that weekly dosing required 6 months of therapy to achieve a steady state. Alternatively, if the weekly dose was administered daily for 5 consecutive days (six patients), the steady state could be achieved in the first week. Mean steady state

Pharmacokinetics of Immunoglobulin

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A
1200

Serum IgG (mg/dL)

1000 800 600 400 200 0 -1 0 1 2 3 4 5 6 7 8

Time (days)

B
Increase in IgG (mg/dL)
400 300 200 100 0 -100 -200 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Time (days)
Fig. 4. Serum IgG levels during SCIG therapy. (A) Weekly infusions. The IgG levels vary, on average, les than 10% over the week in between infusions. Data are mean SD; n 5 41 for all points except day 5 (n 5 40). (From Berger M. Subcutaneous IgG therapy in immune deficiency diseases. In: Clinical focus on primary immune deficiencies, issue 13. Townson (MD): Immune Deficiency Foundation; 2008. p. 2; with permission.) (B) Biweekly infusions. The IgG level varies more than it does with weekly infusions, but not as much as with IVIG. The absorption is still blunted in comparison to IVIG. Data are medians and ranges at each time point (n 5 12). (From Gustafson R, Gardulf A, Hansen S, et al. Rapid subcutaneous immunoglobulin administration every second week results in high and stable serum immunoglobulin G levels in patients with primary antibody deficiencies. Clin Exp Immunol 2008;152:277; with permission.)

trough levels of IgG ranged from 950 to 1120 mg/dL and did not differ in patients who were previously treated with IMIG or IVIG (17 patients) when compared with patients who were previously IgG nave (6 patients). The actual rate of catabolism and bioavailability of SCIG in this study can only be estimated because of the inability to know precisely the rate of endogenous IgG production. In the eight patients who had the lowest pretreatment IgG levels, the calculated fractional catabolic rate assuming 100% bioavailability was between 4.1% 1.0 (mean SD) and 4.4 1.1% per day, only slightly lower than the rate calculated in normal individuals in tracer studies (see Table 1). The lower rate of catabolism might be explained by the lower endogenous IgG levels in these patients who have PID. In another subgroup of six patients with higher pretreatment (but still subnormal) IgG levels, calculated daily fractional catabolic rate was roughly similar, ranging from 4.0 0.6% to 6.3 1.4%. If bioavailability was, in fact, significantly less than 100%, then the calculated fractional catabolic rate would have been lower and would have indicated more significant impairment of IgG catabolism, although perhaps still consistent with some of the longer half-lives reported with

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IVIG. The bioavailability of SCIG has not been determined precisely. The authors noted that IgG subclass levels in patients receiving SCIG differed slightly from the proportions in the infused product. Levels of IgG1 and IgG3 were slightly lower, whereas levels of IgG2 were slightly higher. Levels of IgG4 were low in the product and in patients. The significance of these subtle differences was unclear. Only one product is licensed specifically for SC administration in the United States (Vivaglobin, CSL Behring, King of Prussia, Pennsylvania), although any product suitable for IV administration with concentration of 10% or more or IMIG also may be administered SC.2 In the licensing studies for Vivaglobin, patients were switched from IVIG to SCIG under a protocol that called for dose adjustment of the SC product to give a time-averaged area under the curve that was equivalent to what had been obtained previously with IVIG. This change required administration of an average of 1.37 times (range 1.021.92) the IV dose by the SC route.48 The mean trough IgG levels were 768 mg/dL on IVIG, which rose to 1040 mg/dL on SCIG. A rise in the trough IgG level is expected, because the plasma concentration curve is flattened out with SCIG in comparison to IVIG (see Fig. 3B, Fig. 4A). It is also likely, however, because initial phases of catabolism of IVIG are more rapid as the concentration is supraphysiologic. There is a cost of a certain amount of IVIG that is catabolized rapidly to provide an intravascular bolus to fill the extravascular space quickly to create a reservoir for the period between doses and prevent the trough level from falling too low. SCIG maintains a more physiologic balance between the intravascular and extravascular compartments and can maintain a higher IgG trough level with overall lower amounts of IgG per unit time. The most recent analysis of SCIG pharmacokinetics included 12 patients (11 common variable immunodeficiency, 1 X-linked agammaglobulinemia) given a 16% concentration SCIG product at a dose of 0.2 g/kg every 2 weeks.49 These authors calculated a median half-life of 40.6 days (95% CI 20.156.1 days) for total IgG and 23.3 days (95% CI 12.731.3 days) for tetanus antibody. They speculated (as have others) that endogenous IgG production could lead to a slower rate of disappearance of total IgG, which would not occur in the case of tetanus antibody. The IgG level fluctuated somewhat more between infusions, in comparison to what has been observed with weekly dosing (Fig. 4B).
SUMMARY

IgG equilibrates between intra- and extravascular compartments, and its catabolism is controlled by a complex concentration-dependent endocytic mechanism mediated by FcRn. Studies using radioactive labeled IgG in healthy adults indicated an elimination half-life of approximately 23 days, with a lower value for IgG3 of 7 days. A twocompartment pharmacokinetic model fits the data in several studies of bolus IgG replacement therapy but is not universally applied in studies of IgG decay rates. This difference between studies, together with other methodologic variables (including dose, interval, sampling schedules and duration, method of measurement of IgG, and possible actual individual variation in the catabolism of IgG), yields a large range of calculated decay rates: 20 to 60 days for total IgG across studies of IVIG. The same variability is seen when measuring IgG subclasses individually, and the distinct properties (shorter half-life) of IgG3 seen in tracer studies are not as apparent in studies of IVIG or SCIG replacement pharmacokinetics. Most studies of IVIG in neonates tend to show somewhat shorter half-lives ranging from 10 to 40 days, although the largest study to date yielded results similar to adults. Decay rates determined by specific antibody measurements in adults give results similar to total IgG, whereas in neonates the half-lives are significantly shorter. The

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half-life of IVIG seems to be short in patients with severe burns and patients who have undergone bone marrow transplantation, which is not likely to be entirely explained by methodologic variables. Alternatively, studies of IVIG in malignancies such as chronic lymphocytic leukemia and multiple myeloma suggest that reduced IgG catabolism may lead to a longer half-life of IVIG, but this has not been established clearly. SCIG leads to more physiologic IgG levels because the peaks and nadirs between infusions are blunted by slow absorption and maintenance of closer equilibrium between intra- and extravascular compartments. Although SCIG is usually given weekly (sometimes more often), a recent study suggests that a 2-week interval is also practical. Because of the individual variability of IgG kinetics and distinct alterations in certain disease states, periodic measurement of IgG trough levels is essential during replacement therapy, regardless of the route of administration.

REFERENCES

1. Orange JS, Hossny EM, Weiler CR, et al. 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. J Allergy Clin Immunol 2006;117:S52553. 2. Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol 2004;112:17. 3. Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy 1969; 13:1110. 4. Waldmann TA, Strober W, Blaese RM. Variations in the metabolism of immunoglobulins measured by turnover rates. In: Merler E, editor. Immunoglobulins. Washington, DC: National Academy of Sciences; 1970. p. 3351. 5. Brambell FW, Hemmings WA, Morris IG. A theoretical model of gamma-globulin catabolism. Nature 1964;203:13524. 6. Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A 1996;93:55126. 7. Simister NE, Mostov KE. An Fc receptor structurally related to MHC class I antigens. Nature 1989;337:1847. 8. Leach JL, Sedmak DD, Osborne JM, et al. Isolation from human placenta of the IgG transporter, FcRn, and localization to the syncytiotrophoblast: implications for maternal-fetal antibody transport. J Immunol 1996;157:331722. 9. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007;7:71525. 10. Sachs UJ, Socher I, Braeunlich CG, et al. A variable number of tandem repeats polymorphism influences the transcriptional activity of the neonatal Fc receptor alpha-chain promoter. Immunology 2006;119:839. 11. Waldmann TA, Terry WD. Familial hypercatabolic hypoproteinemia: a disorder of endogenous catabolism of albumin and immunoglobulin. J Clin Invest 1990;86: 20938. 12. Wani MA, Haynes LD, Kim J, et al. Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proc Natl Acad Sci U S A 2006;103:50849. 13. Zhou H. Clinical pharmacokinetics of etanercept: a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein. J Clin Pharmacol 2005;45:4907.

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14. Koleba T, Ensom MH. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy 2006;26:81327. 15. Alyanakian MA, Bernatowska E, Scherrmann JM, et al. Pharmacokinetics of total immunoglobulin G and immunoglobulin G subclasses in patients undergoing replacement therapy for primary immunodeficiency syndromes. Vox Sang 2003;84:18892. 16. Ballow M, Berger M, Bonilla FA, et al. Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%). Vox Sang 2003;84:20210. 17. Berger M. A multicenter, prospective, open label, historically controlled clinical trial to evaluate efficacy and safety in primary immunodeficiency diseases (PID) patients of Flebogamma 5% DIF, the next generation of Flebogamma. J Clin Immunol 2007;27:62833. 18. Berger M, Pinciaro PJ. Safety, efficacy, and pharmacokinetics of Flebogamma 5% [immune globulin intravenous (human)] for replacement therapy in primary immunodeficiency diseases. J Clin Immunol 2004;24:38996. 19. Borte M, Davies SV, Touraine J-L, et al. Clinical properties of a novel liquid intravenous immunoglobulin: studies of patients with immune thrombocytopenic purpura and primary immunodeficiencies. Transfus Med Hemother 2004;31: 12634. 20. Church JA, Leibl H, Stein MR, et al. Efficacy, safety and tolerability of a new 10% liquid intravenous immune globulin [IGIV 10%] in patients with primary immunodeficiency. J Clin Immunol 2006;26:38895. 21. Ochs HD, Pinciaro PJ. Octagam 5%, an intravenous IgG product, is efficacious and well tolerated in subjects with primary immunodeficiency diseases. J Clin Immunol 2004;24:30914. 22. Privigen. Prescribing information. King of Prussia (PA): CSL Behring; 2008. 23. Schiff RI, Rudd C. Alterations in the half-life and clearance of IgG during therapy with intravenous gamma-globulin in 16 patients with severe primary humoral immunodeficiency. J Clin Immunol 1986;6:25664. 24. Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. 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. Ann Intern Med 2001;135:16574. 25. Mankarious S, Lee M, Fischer S, et al. The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin. J Lab Clin Med 1988;112:63440. 26. Shirani KZ, Vaughan GM, McManus AT, et al. Replacement therapy with modified immunoglobulin G in burn patients: preliminary kinetic studies. Am J Med 1984; 76:17580. 27. Hansbrough JF, Miller LM, Field TO Jr, et al. High dose intravenous immunoglobulin therapy in burn patients: pharmacokinetics and effects on microbial opsonization and phagocytosis. Pediatr Infect Dis J 1988;7:S4956. 28. Chirico G, Rondini G, Plebani A, et al. Intravenous gammaglobulin therapy for prophylaxis of infection in high-risk neonates. J Pediatr 1987;110:43742. 29. Kinney J, Mundorf L, Gleason C, et al. Efficacy and pharmacokinetics of intravenous immune globulin administration to high-risk neonates. Am J Dis Child 1991; 145:12338. 30. Kyllonen KS, Clapp DW, Kliegman RM, et al. Dosage of intravenously administered immune globulin and dosing interval required to maintain target levels of immunoglobulin G in low birth weight infants. J Pediatr 1989;115:10136.

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31. Noya FJ, Rench MA, Courtney JT, et al. Pharmacokinetics of intravenous immunoglobulin in very low birth weight neonates. Pediatr Infect Dis J 1989;8:75963. 32. Noya FJ, Rench MA, Garcia-Prats JA, et al. Disposition of an immunoglobulin intravenous preparation in very low birth weight neonates. J Pediatr 1988;112:27883. 33. Weisman LE, Fischer GW, Hemming VG, et al. Pharmacokinetics of intravenous immunoglobulin (sandoglobulin) in neonates. Pediatr Infect Dis 1986;5:S18188. 34. Weisman LE, Fischer GW, Marinelli P, et al. Pharmacokinetics of intravenous immunoglobulin in neonates. Vox Sang 1989;57:2438. 35. Weisman LE, Stoll BJ, Kueser TJ, et al. Intravenous immune globulin prophylaxis of late-onset sepsis in premature neonates. J Pediatr 1994;125:92230. 36. Jenson HB, Pollock BH. Meta-analyses of the effectiveness of intravenous immune globulin for prevention and treatment of neonatal sepsis. Pediatrics 1997;99:E2. 37. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database Syst Rev 2000:CD000361. 38. Groothuis JR, Levin MJ, Rodriguez W, et al. Use of intravenous gamma globulin to passively immunize high-risk children against respiratory syncytial virus: safety and pharmacokinetics. The RSVIG Study Group. Antimicrob Agents Chemother 1991;35:146973. 39. Bosi A, De Majo E, Guidi S, et al. Kinetics of anti-CMV antibodies after administration of intravenous immunoglobulins to bone marrow transplant recipients. Haematologica 1990;75:10912. 40. Cottler-Fox M, Lynch M, Pickle LW, et al. Some but not all benefits of intravenous immunoglobulin therapy after marrow transplantation appear to correlate with IgG trough levels. Bone Marrow Transplant 1991;8:2733. 41. Hagenbeek A, Brummelhuis GJ, Donkers A, et al. Rapid clearance of cytomegalovirus-specific IgG after repeated intravenous infusions of human immunoglobulin into allogeneic bone marrow transplant recipients. J Infect Dis 1987;155:897902. 42. Rand KH, Gibbs K, Derendorf H, et al. Pharmacokinetics of intravenous immunoglobulin (Gammagard) in bone marrow transplant patients. J Clin Pharmacol 1991;31:11514. 43. Rand KH, Houck H, Ganju A, et al. Pharmacokinetics of cytomegalovirus specific IgG antibody following intravenous immunoglobulin in bone marrow transplant patients. Bone Marrow Transplant 1989;4:67983. 44. Chapel HM, Hargreaves R, Lee M, et al. Intravenous immunoglobulin therapy in patients with multiple myeloma. Immunodeficiency 1993;4:778. 45. Sklenar I, Schiffman G, Jonsson V, et al. Effect of various doses of intravenous polyclonal IgG on in vivo levels of 12 pneumococcal antibodies in patients with chronic lymphocytic leukaemia and multiple myeloma. Oncology 1993;50:46677. 46. Smith GN, Griffiths B, Mollison D, et al. Uptake of IgG after intramuscular and subcutaneous injection. Lancet 1972;1:120812. 47. Waniewski J, Gardulf A, Hammarstrom L. Bioavailability of gamma-globulin after subcutaneous infusions in patients with common variable immunodeficiency. J Clin Immunol 1994;14:907. 48. Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol 2006;26:26573. 49. Gustafson R, Gardulf A, Hansen S, et al. Rapid subcutaneous immunoglobulin administration every second week results in high and stable serum immunoglobulin G levels in patients with primary antibody deficiencies. Clin Exp Immunol 2008;152:2749.

Self - infusion Programmes for I mmuno globulin Replacement at Home : Feasibility, Safety a nd Efficac y
Malini V. Bhole, MSc, MRCPCH, MD, Janet Burton, MSc, RQN, Helen M. Chapel, MA, MP, FRCP, FRCPATH*
KEYWORDS  IVIg  SCIg  Self-infusion  Home therapy

Since the first paper was written on the use of therapeutic immunoglobulins in patients,1 great progress has been made in immunoglobulin therapy, including the manufacturing processes, types of products available, routes of administration, and safety and efficacy of self-infusion at home. Currently, immunoglobulin replacement can be achieved effectively via intravenous (IVIg) or subcutaneous (SCIg) administration. Both options have been shown to be safe and equally efficacious in decreasing the incidence and severity of infections in patients with antibody deficiencies.2 Additionally, high-dose immunoglobulin therapy is used in a range of medical conditions, and patients can be trained to self-administer these infusions at home. This article discusses the feasibility and development of successful home therapy programs along with safety, efficacy, and cost-effectiveness.
HISTORICAL BACKGROUND

Regular replacement with immunoglobulin infusions is the mainstay of treatment in patients with antibody deficiency. Once preparations of immunoglobulin (IVIg) that were safe to administer intravenously became available, large doses could be given to maintain adequate serum IgG levels to prevent infection. In most patients, monthly doses of 300 to 400 mg/kg body weight were sufficient to achieve immunoglobulin

Department of Clinical Immunology, Nuffield Department of Medicine and Oxford Radcliffe Hospitals, Oxford, UK * Corresponding author. Level 4A Academic Street, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK. E-mail address: helen.chapel@ndm.ox.ac.uk (Helen M. Chapel).
Immunol Allergy Clin N Am 28 (2008) 821832 doi:10.1016/j.iac.2008.06.005 immunology.theclinics.com 0889-8561/08/$ see front matter. Crown Copyright 2008 Published by Elsevier Inc. All rights reserved.

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levels above the lower limit of the normal range,3 although monthly infusions often resulted in wide fluctuations between the peak and trough levels. A steadier state was achievable by administering the same total monthly dose in divided doses at shorter intervals. An increased frequency of infusions resulted directly in increased costs of treatment, both in terms of hospital resources and patient time (time off school or work). Home therapy for IVIg administration was first introduced as a measure to achieve a satisfactory balance among adequate treatment, patient convenience, and cost-effectiveness. Based on the vast experience of patients with hemophilia who were self-administering factor VIII at home for many years,48 home therapy programs for IVIg were investigated in the United States in the early 1980s912 and were quickly adapted in the United Kingdom.13 Despite the reduction in costs that results from avoidance of the need for hospital space and staff, home therapy programs did not become popular outside of the United States and the United Kingdom until recently. Some countries banned such programs on safety or moral grounds (patients should not be taught to perform venepuncture), whereas other health care systems did not adapt easily to medical treatment without direct supervision. The UK Department of Health was willing to give approval in 1986, provided that there was ongoing data collection regarding safety and efficacy. Feasibility had already been proven in the hemophilia community, and professional home care companies were providing products and consumables for patients to treat themselves with hemophilia products, renal dialysis facilities, orin the case of HIV patientsintravenous antibiotics at home. Once immunoglobulin therapy by the subcutaneous route (SCIg) was established in the early 1990s, self-infusion for SCIg became widespread. Originally, subcutaneous infusions of immunoglobulin were done in the late 1970s with products designed for intramuscular use and a slow infusion rate.1422 This method was abandoned as the infusions were accompanied by multiple reactions, sterile abscesses associated with mercury used as a preservative, long infusion times, and also required inefficient battery-operated pumps. There was renewed interest in the early 1990s after technical improvements in the available products, infusion pumps, and protocols,2326 particularly in Sweden,24,27,28 because the use of IVIg was banned there by the government at that time after an outbreak of transmitted hepatitis C in IVIg. Once new methods of viral inactivation were introduced and the efficacy of SCIg for infection prevention had been proven to match that of IVIG in immunodeficient patients,2 studies in Sweden showed safety and cost-effectiveness. Since then, the use of subcutaneous immunoglobulin has increased exponentially. Increased interest in the use of the subcutaneous route for immunoglobulin replacement has led to further development of products specifically intended for subcutaneous use. A survey conducted by the European Society for Immunodeficiency in 2002 reported that 7% of European patients were on regular immunoglobulin replacement by the subcutaneous route, indicating the rapid expansion of the use of SCIg in Europe.29
FEASIBILITY OF SELF-INFUSIONS

Neither intramuscular immunoglobulin injections nor the slow administration of immunoglobulins subcutaneously was feasible or sufficiently safe to use at home. The intravenous route was the method of choice for self-administration in the 1980s. The widespread use of self-administration for other products and the changing culture of health care in many countries made this approach feasible for IVIg therapy. Professional medical bodies in the United Kingdom and health care providers in the United States and United Kingdom recommended that the concept be proven safe and

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required that patients be entered into recognized programs in which they were formally trained. Training involved the practice of venepuncture to secure venous access, the availability of a suitable infusion partner in case of a reaction at home, and proof of understanding by the patient and the partner of the potential side effects of intravenous administration of IVIg. Using training protocols, this approach proved to be feasible, safe, and efficacious in adults and children.911,13,30,31 All patients who required immunoglobulin replacement therapy were not suitable for home therapy programs for various reasons, including poor venous access, personal circumstances, or lack of a suitable infusion partner. Introduction of rapid subcutaneous replacement protocols since 1991 has increased the number of patients in home therapy programs, because SCIg obviates the need for venous access and, in some countries, the immediate need for an infusion partner on site.24,32 The practice of immunoglobulin replacement differs from country to country. In the United Kingdom, newly diagnosed patients are loaded rapidly with weekly IVIg and, if suitable, are enrolled into a home therapy program as soon as they are stable on immunoglobulin therapy. The choice of route for immunoglobulin infusions depends on several factors, including platelet count, amount of subcutaneous tissue available, dose of immunoglobulin required to prevent infections, and ease of venous access. Practice differs in Sweden, where even newly diagnosed patients are started on subcutaneous replacement and all patients are subsequently trained to self-infuse at home. The availability of two equally efficacious and safe routes of immunoglobulin replacement allows flexibility of choice that is adaptable to the various stages of life. Children may prefer the subcutaneous route but revert to IVIg in their teenage years to lessen the infusion frequency. Once independent, however, they often prefer to undertake SCIg until they are unable to self-infuse and revert to IVIg in the clinic setting in older age. Such choice and adaptability improve the overall quality of life.
EFFICACY OF HOME INFUSIONS

The evidence that regular replacement immunoglobulin (in any setting) reduces the incidence and severity of infections in patients with antibody deficiency has been previously reported. It was important to show that it applied to those infusing at home too. In the first report with home therapy and self-administration of IVIg, Ochs and colleagues11 reported 1.7 infections per patient per year compared to 2.5 infections/patient/year in the previous year of hospital-based infusions. The reduction in infections was probably secondary to shortening the interval between doses (10 to 15 days versus 4 weeks), resulting in a higher IgG trough level and similar differences between peak and trough levels. This improved efficacy with shorter intervals was only feasible with the home therapy program at that time because of scarcity of hospital facilities and staff. Similar efficacy in infection prevention for immunoglobulin usage at home was reported by other investigators, and figures for adults and children were similar.2,9 Although equal numbers of days were lost from school or work because of illness, days lost from work by patients or parents for infusion attendances were considerably reduced.13 Kobayashi and colleagues31 reported successful home administration of IVIg by parents for 12 children aged 2 to 17, with no difference in the frequency and severity of infections when compared to the previous phase of IVIg in a clinic setting. Self-administered SCIg is equal in efficacy to IVIg in terms of trough levels and infection rates. A multicenter randomized crossover study of 40 patients who received IVIg or SCIg for a year before crossing over to the alternative mode of delivery showed comparable trough levels in both phases.2 There were no significant differences in the numbers of infections between the two treatments. Outcome was measured using

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infection scores, which took into account the frequency and severity of infections. Outcomes for patients who self-infused at home were no different from outcomes for patients who received their therapies in the clinic. Two other trials that independently compared retrospective data for IVIg when patients were transferred to SCIg (in Europe, Brazil, and North America) reported the incidence of serious bacterial infections as 0.04/patient/year and the overall annual incidence of all minor plus major infections as 4.4/patient.26,34 The data from patients in Europe and the United States were slightly different because of the use of an increased dose of SCIg in the United States (namely, 137% of that used intravenously), whereas European studies used the same cumulative doses (g/kg/mo) for both routes. Overall, the data from patients on home therapy with SCIg showed increased protection against serious infections as well as a reduction in self-reported infections.28,3538 Efficacy depends on compliance, and subjective and objective monitoring of compliance is essential. In the United Kingdom, compliance is evidenced by maintenance of serum IgG trough levels on blood samples taken by the patient immediately before the infusion and returned to the center by mail for measurement of trough IgG levels. IgA and IgM levels are also measured to check for reversal or progression of immunodeficiency. C-reactive protein gives a measure of ongoing inflammation (usually in the lungs or gastrointestinal tract), and liver function tests are done for early detection of possible transmission of hepatitis viruses.
SAFETY

The safety profile of immunoglobulin replacement treatment at home is crucial. It includes the absence of infusion-related adverse reactions and reactions caused by possible transmitted infections, because home therapy programs result in less frequent attendance at hospital for medical follow-up. The first prospective study of adverse reactions in patients self-infusing IVIg at home was a multicenter study in the United Kingdom with 119 patients.30 No serious reactions were reported. Only 19 moderate adverse reactions were recorded from 2031 infusions (0.7%), all of which resolved without medical aid. Further analysis showed that most were related to pre-existing infections and were avoidable, giving a rate of 0.5% for adverse reactions. This study was further extended to include a total of 459 patients from centers across the United Kingdom. The rate of adverse reactions in the larger study remained consistent at 0.7%,39 still without any serious reactions. The high safety profile of SCIg makes it another appropriate route for self-administration at home. In addition to ongoing infection, accidental infusion into small blood vessels has been reported as a possible explanation of moderate systemic reaction in one patient.35 Several studies from many centers across the world have endorsed the safety of self-administration of SCIg at home.2,2327,34,35,40,41 SCIg has been used successfully with minimal adverse reactions in patients with previous severe reactions to IVIg. It also has been used safely in patients with anti-IgA antibodies,4244 although the actual significance of anti-IgA antibodies remains unclear. The safety and efficacy of self-administered SCIg and IVIg have been demonstrated during pregnancy,15,24,45 although the site for SCIg infusions likely changes from the abdomen to the upper thigh.
QUALITY OF LIFE

One of the major impacts of self-administered immunoglobulin replacement at home has been on the quality of life of patients with primary antibody deficiencies. Since the introduction of home therapy programs, most patients in countries that have adopted

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home therapy have indicated their preference to receive their infusions at home. The reasons and benefits suggested from oral responses from patients are increased selfconfidence, better understanding of their condition, greater independence, improved disease control, decreased loss of time from school or work, decreased cost, and minimal disruption of daily activities.10,12 Peer group support has been proposed as an unexpected but important benefit of home training programs. One of the early studies to evaluate patient responses to home treatment systematically was a multicenter study based on analysis of completed questionnaires.46 The Life Quality Index, developed by investigators specifically for patients undergoing IVIg treatment, assessed quality of life. A similar questionnaire-based study from a Swedish group showed that weekly self-administered SCIg led to improved quality of life as measured by better functional status, improved general health, higher trough levels leading to fewer breakthrough infections, and more patient independence.28,47 Different outcome questionnaires or instruments have been used in published reports, including Life Quality Index, Medical Outcomes Study 36-Item Short Form Health Survey, and the Child Health Questionnaire Parental Form. (For a detailed list of available questionnaires, see reference.48) The most complete studies have used standardized survey questionnaires as tools to measure health-related quality of life, which is defined as a subjective perception of the impact of disease and treatment on daily life, including physical, psychological, and social aspects.49 The other important measure of patient-reported outcome is treatment satisfaction, as defined by patients reports on their treatment experience and satisfaction toward the treatment, encouraging patient compliance.50,51 Studies from Sweden and the United States have demonstrated that immunoglobulin replacement dramatically improved the results of health-related quality of life, bringing it on par with normal population.47,52 Patients reported fewer infections and decreased anxiety regarding their health. Further improvement in health-related quality of life and treatment satisfaction has been achieved with the relative ease and safety of self-administered SCIg. Technical improvements in available products and infusion pumps have had a favorable impact on the overall quality of life among adults and children with primary antibody deficiencies. As with patients on IVIg, patients on SCIg report an increased sense of self-control, increased flexibility of treatment with minimal disruption of daily life, decreased time off work or school, improved family relations, and greater well being.23,24,28,32,3638,40,46,47,53
COST-EFFECTIVENESS OF SELF-INFUSIONS AT HOME

In addition to being a safe and efficacious treatment option with significant improvement in the quality of life, self-infusions at home may reduce the overall costs of treatment for patients and health care providers, depending on the health care system. Early reports of home infusions from the United States estimated savings of between $195 and $355 per infusion.11,31 This calculation was based on savings from clinic charges, pharmacy expenses, and professional fees and excluded transportation costs and time lost from work/school. In 1988, Ryan and colleagues54 reported that within the UK National Health Service, the annual cost per patient was 884 for hospital therapy compared to 601 for the first year of home therapy and 530 for subsequent years, although this study did not include the cost of the immunoglobulin product. In contrast, Sorensen and colleagues12 included the additional processing costs for immunoglobulin home delivery and noted no cost savings between hospital infusions and home therapy in the United States. A health-economic evaluation of immunoglobulin therapy done in Sweden reported savings of approximately $10,000 per

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patient per year on changing from hospital-based IVIg to self-infused SCIg at home,27 and similar savings were reported from other countries.40,55 Because most of these calculations depended on a differential in the price of the relevant products and place of prescribing, however, and as this is no longer the case, these studies need repeating.
EXTENSION OF HOME THERAPY PROGRAMS

High-dose immunoglobulin is used increasingly for immunomodulation in autoimmune diseases. To maintain a reasonable and functional quality of life, patients require higher doses of immunoglobulin treatment at regular intervals. The experience gained from successful home therapy programs for patients with primary antibody deficiencies has encouraged some centers to offer training in self-infusions to these patients.5659 As with primary immunodeficiencies, self-administered infusions at home allow optimal disease control and vastly improve quality of life for patients with potentially debilitating conditions.
REQUIREMENTS FOR A SELF-INFUSION HOME THERAPY PROGRAM

A successful home care program for self-infusion of immunoglobulin depends on several factors, including general acceptability of home treatments, perception of need by patients, and an expert and dedicated team to provided the service (Box 1). In particular, the initiation and successful continuation of an efficient home therapy program requires planning in terms of funding and practicalities. These factors include resources and training for staff, criteria for patient selection, protocols for patient training and regular monitoring, organization of regular supply of product and consumables, support staff (including specialist nurses and clinical immunologists), and general support from relevant disease-specific patient organizations.
Planning

The best team to provide home therapy service is one that is already involved in immunoglobulin replacement therapy within the hospital setting. This ensures longterm continuity of care and support for the patients. Self-infusion at home for most patients enables more cost-effective use of available resources. Before starting a patient on such a program, it is important to secure funding to ensure ongoing and timely supply of the immunoglobulin product and the service on a long-term basis. The mechanisms differ from country to country depending on the existing health care system, regardless of whether the source of funds is the government, a health care provider, or medical insurance companies.

Box 1 Factors that influence a successful home treatment program  General acceptability of treatments at home  Acceptance of legalities and liabilities involved by the existing health care system  High degree of motivation on the part of the patients  Educational resources for teaching patients all aspects of home treatments  Availability of resources to deliver consumables and products to homes  Dedicated and experienced team of doctors and nurses to provide the service

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Staff Resources and Training

Training of medical and nursing staff involved in a home therapy program is directed toward appropriate assessment of patients for self-infusions, ability to translate medical principles in simple terms and demonstrate practical techniques in a patient-friendly way, and the acquisition of appropriate skills for patient monitoring, troubleshooting, and patient support (Box 2).
Patient Selection

Some of the general criteria required for selection of a patient for the home therapy program are listed in Box 3, although practice differs from center to center and country to country. Home therapy may not be suitable in certain groups of patients, especially elderly patients and patients with difficult social or personal circumstances. It is important to undertake a risk assessment for each patient before enrollment into a selfinfusion program. Governments and health care providers have gradually accepted this principle, and IVIg and SCIg are self-infused at home in many European and North American countries rather than infused at home by a trained nurse.
Patient Training

The key aspects of training programs for selected patients and their infusion partners are detailed in Box 4. Training may be undertaken either individually or in small groups. The length of the training period varies depending on the protocol and available resources but must be long enough to ensure proof of competence on the part of the attendees. Patient education includes knowledge about the product used, importance of a hygienic environment and aseptic techniques, correct techniques for selfadministration, precise documentation of infusion logs, and safe disposal methods. Emphasis is placed on the importance of postponing an infusion if the patient is unwell because of increased risk of an adverse event during acute bacterial infection.60 Patients and their partners must be trained to recognize adverse reactions and know the immediate measures required to treat such a reaction. Documentation of direct observation, assessment of competency, and feedback is essential at each stage.
Resources at Home

There are no particular requirements for resources at home other than the timely and regular supply of the immunoglobulin product and other consumables required for home administration. Inclusion of a method for safe disposal of clinical waste and sharps bins is important, as well as the completion of monitoring and infusion logs. Patients are required to complete infusion logs recording details of infusions and batch

Box 2 Training and teaching skills to be acquired by immunology staff  Ability to assess suitability of patients for home therapy  Ability to translate basic medical science and understanding to patients and their infusion partners  Ability to explain principles and practicalities of self-administration of immunoglobulins, such as aseptic technique, venipuncture, and blood sampling  Acquisition of knowledge and skills required for patient monitoring  Ability to troubleshoot and provide patient support

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Box 3 Criteria for patient selection  Ability to understand the basic principles and practicalities involved  High degree of motivation and reliability  Presence of a suitable infusion partner to understand the basic principles and provide appropriate support for the procedure  Technical skills of patient and infusion partner  Ease and availability of IV access for IVIg  Suitable home environment (eg, general hygiene, area for infusing, pets)  Availability of appropriate storage space for product and consumables (may need a refrigerator)  Availability of immediate telephone access in case of emergency

numbers of the immunoglobulin used in the case of need for urgent look-back, as followed the outbreak of hepatitis C in 1994.61 In some countries these logs are completed on Web-based systems, but paper records are equally satisfactory. Patients may maintain regular symptom diaries and, in the United Kingdom, are required to organize regular blood tests every 6 to 12 weeks for trough immunoglobulin levels, liver function tests, and C-reactive protein levels. In addition to regular medical followup consultations, reviews by nursing staff are important to check for the maintenance of practical skills.
Specialist Support

Advice and support are often needed for patients on home therapy programs, especially in the event of practical infusion problems, during intermittent infections, or

Box 4 Key aspects of patient training and education  Knowledge of the nature of product used, current dose/volume required  Importance of a hygienic environment, including sterility of work surfaces and consumables throughout the infusion  Correct technique of self-administration, including Noting batch numbers and expiry date Reconstituting product where required Priming of giving sets Showing venipuncture skills Monitoring drip rates during infusion  Precise documentation of infusion logs  Prompt recognition of adverse reactions both minor and major  Immediate steps to be taken in the event of an adverse reaction  Safe disposal methods

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during periods of stress or illness. An experienced medical member of the specialist team must be available at all times.
General Support

Patients are encouraged to join the relevant national patient organization and share their experiences and concerns with others. Peer group support is important for the development of coping skills and improvement in quality of life. Protocols around the world have developed on similar lines, and most centers follow these principles despite variations in health care provision in different countries.12,31 In addition, guidelines and protocols around the world have been developed on similar lines, and most centers follow these principles despite variations in healthcare provision in different countries.33,53
SUMMARY

This review of the currently available literature from more than two decades of clinical experience with self-infusions of immunoglobulin at home provides evidence to support the feasibility, safety, and efficacy in all age groups. Self-infusions at home not only increase patient confidence and their understanding of immunodeficiency but also contribute to the improvement of health-related quality of life. Such home therapy programs should be encouraged, and wherever possible, experienced centers should extend their services to include patients who require immunoglobulin therapy for immunomodulation. Home therapy programs play an important role in the long-term health outcome.
ACKNOWLEDGMENTS

Many individuals have contributed to the development of programs throughout the world for more than 30 years. In our center we owe a special debt of gratitude to Sister Veronica Brennan, who established the first home therapy training center in the United Kingdom and subsequently helped other centers here and in Europe to set up similar programs.
REFERENCES

1. Bruton OC. Agammaglobulinemia. Pediatrics 1952;9:7228. 2. Chapel HM, Spickett GP, Ericson D, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 2000;20:94100. 3. Morell A, Schnoz M, Barandun S. Build-up maintenance of IgG serum concentrations with intravenous immunoglobulin in patients with primary humoral immunodeficiency. Vox Sang 1982;43:2129. 4. Evensen SA, Thaule R, Groan K. Self-therapy for haemophilia in Norway: effect on transfusion frequency and days lost from work. Acta Med Scand 1979;205:3959. 5. Ingram GI, Dykes SR, Creese AL, et al. Home treatment in haemophilia: clinical, social and economic advantages. Clin Lab Haematol 1979;1:1327. 6. Kaufert JM. Social and psychological responses to home treatment of haemophilia. J Epidemiol Community Health 1980;34:194200. 7. Levine PH. Efficacy of self-therapy in hemophilia: a study of 72 patients with hemophilia A and B. N Engl J Med 1974;291:13814. 8. Rizza CR, Spooner RJ. Home treatment of haemophilia and Christmas disease: five years experience. Br J Haematol 1977;37:5366.

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9. Ashida ER, Saxon A. Home intravenous immunoglobulin therapy by self-administration. J Clin Immunol 1986;6:3069. 10. Ochs HD, Fischer SH, Lee ML, et al. Intravenous immunoglobulin home treatment for patients with primary immunodeficiency diseases. Lancet 1986;1:6101. 11. Ochs HD, Lee ML, Fischer SH, et al. Self-infusion of intravenous immunoglobulin by immunodeficient patients at home. J Infect Dis 1987;156:6524. 12. Sorensen RU, Kallick MD, Berger M. Home treatment of antibody-deficiency syndromes with intravenous immune globulin. J Allergy Clin Immunol 1987;80:8105. 13. Chapel H, Brennan V, Delson E. Immunoglobulin replacement therapy by selfinfusion at home. Clin Exp Immunol 1988;73:1602. 14. Bayston K, Leahy MF, McCreanor JD, et al. Subcutaneous gammaglobulin: effective management of hypogammaglobulinaemia. N Z Med J 1985;98:652. 15. Berger M, Cupps TR, Fauci AS. High-dose immunoglobulin replacement therapy by slow subcutaneous infusion during pregnancy. JAMA 1982;247:28245. 16. Berger M, Cupps TR, Fauci AS. Immunoglobulin replacement therapy by slow subcutaneous infusion. Ann Intern Med 1980;93:556. 17. Leahy MF. Subcutaneous immunoglobulin home treatment in hypogammaglobulinaemia. Lancet 1986;2:48. 18. Roord JJ, van der Meer JW, Kuis W, et al. Home treatment in patients with antibody deficiency by slow subcutaneous infusion of gammaglobulin. Lancet 1982;1:68990. 19. Stiehm ER, Casillas AM, Finkelstein JZ, et al. Slow subcutaneous human intravenous immunoglobulin in the treatment of antibody immunodeficiency: use of an old method with a new product. J Allergy Clin Immunol 1998;101:8489. 20. Ugazio AG, Duse M, Plebani A, et al. Subcutaneous infusion of gamma globulins in the management of agammaglobulinemic patients. Birth Defects Orig Artic Ser 1983;19:2135. 21. Ugazio AG, Duse M, Re R, et al. Subcutaneous infusion of gammaglobulins in management of agammaglobulinaemia. Lancet 1982;1:226. 22. Welch MJ, Stiehm ER. Slow subcutaneous immunoglobulin therapy in a patient with reactions to intramuscular immunoglobulin. J Clin Immunol 1983;3:2856. 23. Abrahamsen TG, Sandersen H, Bustnes A. Home therapy with subcutaneous immunoglobulin infusions in children with congenital immunodeficiencies. Pediatrics 1996;98:112731. 24. Gardulf A, Hammarstrom L, Smith CI. Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet 1991;338: 1626. 25. Thomas MJ, Brennan VM, Chapel HH. Rapid subcutaneous immunoglobulin infusions in children. Lancet 1993;342:14323. 26. Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies: a prospective, multi-national study. J Clin Immunol 2006;26:17785. 27. Gardulf A, Andersen V, Bjorkander J, et al. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 1995; 345:3659. 28. Gardulf A, Bjorvell H, Andersen V, et al. Lifelong treatment with gammaglobulin for primary antibody deficiencies: the patients experiences of subcutaneous self-infusions and home therapy. J Adv Nurs 1995;21:91727. 29. Quinti I, Pierdominici M, Marziali M, et al. European surveillance of immunoglobulin safety: results of initial survey of 1243 patients with primary immunodeficiencies in 16 countries. Clin Immunol 2002;104:2316.

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30. Brennan VM, Cochrane S, Fletcher C, et al. Surveillance of adverse reactions in patients self-infusing intravenous immunoglobulin at home. J Clin Immunol 1995; 15:1169. 31. Kobayashi RH, Kobayashi AD, Lee N, et al. Home self-administration of intravenous immunoglobulin therapy in children. Pediatrics 1990;85:7059. 32. Hansen S, Gustafson R, Smith CI, et al. Express subcutaneous IgG infusions: decreased time of delivery with maintained safety. Clin Immunol 2002;104:23741. 33. Roifman CM, Levison H, Gelfand EW. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet 1987;1:10757. 34. Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol 2006;26:26573. 35. Gardulf A, Bjorvell H, Gustafson R, et al. Safety of rapid subcutaneous gammaglobulin infusions in patients with primary antibody deficiency. Immunodeficiency 1993;4:814. 36. Gardulf A, Nicolay U, Math D, et al. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol 2004;114:93642. 37. Kittner JM, Grimbacher B, Wulff W, et al. Patients attitude to subcutaneous immunoglobulin substitution as home therapy. J Clin Immunol 2006;26:4005. 38. Nicolay U, Kiessling P, Berger M, et al. Health-related quality of life and treatment satisfaction in North American patients with primary immunodeficiency diseases receiving subcutaneous IgG self-infusions at home. J Clin Immunol 2006;26: 6572. 39. Brennan VM, Salome-Bentley NJ, Chapel HM. Prospective audit of adverse reactions occurring in 459 primary antibody-deficient patients receiving intravenous immunoglobulin. Clin Exp Immunol 2003;133:24751. 40. Gaspar J, Gerritsen B, Jones A. Immunoglobulin replacement treatment by rapid subcutaneous infusion. Arch Dis Child 1998;79:4851. 41. Radinsky S, Bonagura VR. Subcutaneous immunoglobulin infusion as an alternative to intravenous immunoglobulin. J Allergy Clin Immunol 2003;112:6303. 42. Eijkhout HW, van den Broek PJ, van der Meer JW. Substitution therapy in immunodeficient patients with anti-IgA antibodies or severe adverse reactions to previous immunoglobulin therapy. Neth J Med 2003;61:2137. 43. Gustafson R, Gardulf A, Granert C, et al. Prophylactic therapy for selective IgA deficiency. Lancet 1997;350:865. 44. Sundin U, Nava S, Hammarstrom L. Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy. Clin Exp Immunol 1998;112:3416. 45. Gardulf A, Andersson E, Lindqvist M, et al. Rapid subcutaneous IgG replacement therapy at home for pregnant immunodeficient women. J Clin Immunol 2001;21: 1504. 46. Daly PB, Evans JH, Kobayashi RH, et al. Home-based immunoglobulin infusion therapy: quality of life and patient health perceptions. Ann Allergy 1991;67:50410. 47. Gardulf A, Bjorvell H, Gustafson R, et al. The life situations of patients with primary antibody deficiency untreated or treated with subcutaneous gammaglobulin infusions. Clin Exp Immunol 1993;92:2004. 48. Gardulf A, Nicolay U. Replacement IgG therapy and self-therapy at home improve the health-related quality of life in patients with primary antibody deficiencies. Curr Opin Allergy Clin Immunol 2006;6:43442.

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49. Anderson RT, Aaronson NK, Wilkin D. Critical review of the international assessments of health-related quality of life. Qual Life Res 1993;2:36995. 50. Strasser S, Aharony L, Greenberger D. The patient satisfaction process: moving toward a comprehensive model. Med Care Rev 1993;50:21948. 51. Weaver M, Patrick DL, Markson LE, et al. Issues in the measurement of satisfaction with treatment. Am J Manag Care 1997;3:57994. 52. Howard V, Greene JM, Pahwa S, et al. The health status and quality of life of adults with X-linked agammaglobulinemia. Clin Immunol 2006;118:2018. 53. Sigstad HM, Stray-Pedersen A, Froland SS. Coping, quality of life, and hope in adults with primary antibody deficiencies. Health Qual Life Outcomes 2005;3:31. 54. Ryan A, Thomson BJ, Webster AD. Home intravenous immunoglobulin therapy for patients with primary hypogammaglobulinaemia. Lancet 1988;2:793. 55. Hogy B, Keinecke HO, Borte M. Pharmacoeconomic evaluation of immunoglobulin treatment in patients with antibody deficiencies from the perspective of the German statutory health insurance. Eur J Health Econ 2005;6:249. 56. Koller H, Schroeter M, Feischen H, et al. Subcutaneous self-infusions of immunoglobulins as a potential therapeutic regimen in immune-mediated neuropathies. J Neurol 2006;253:15056. 57. Lee DH, Linker RA, Paulus W, et al. Subcutaneous immunoglobulin infusion: a new therapeutic option in chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 2008;37:4069. 58. Schleinitz N, Jean E, Benarous L, et al. Subcutaneous immunoglobulin administration: an alternative to intravenous infusion as adjuvant treatment for dermatomyositis? Clin Rheumatol 2008;27:10678. 59. Sewell WA, Brennan VM, Donaghy M, et al. The use of self infused intravenous immunoglobulin home therapy in the treatment of acquired chronic demyelinating neuropathies. J Neurol Neurosurg Psychiatr 1997;63:1069. 60. Misbah SA, Chapel HM. Adverse effects of intravenous immunoglobulin. Drug Saf 1993;9:25462. 61. Healey CJ, Sabharwal NK, Daub J, et al. Outbreak of acute hepatitis C following the use of anti-hepatitis C virusscreened intravenous immunoglobulin therapy. Gastroenterology 1996;110:11206.

I mmuno globulin Replacement Therapy in Children

Maria Garcia-Lloret, MD, Sean McGhee, MD, Talal A. Chatila, MD*
KEYWORDS  Intravenous immunoglobulin therapy  Subcutaneous immunoglobulin therapy  Primary immunodeficiency diseases

The benefit of immunoglobulin (IG) replacement in primary antibody deficiencies (AD) is unquestionable. Many of these congenital disorders present early in life and this therapy is often first implemented in the young. For many of these children, IG infusions will remain a requirement for the foreseeable future. No other therapy has demonstrated to be as efficacious as IG in reducing the number and severity of infectious complications in pediatric patients with AD. The consensus among pediatric immunologists is that, when combined with close clinical monitoring, timely and appropriate IG replacement could ultimately extend the life expectancy of these young patients to approach that of the general population. The general concerns surrounding IG therapy affect adults and children equally. Issues regarding efficacy in the ever-expanding applications of IG, the predicted shortages of this drug, and the rising costs of therapy have been comprehensively addressed in a number of recent reviews.15 This article focuses on the indications of IG replacement in children, with an emphasis on the specific diagnostic problems encountered in this population. Also presented is an overview of the practical aspects of IG administration in the pediatric setting, including the recognition and management of adverse reactions. Finally, briefly discussed is the advent of subcutaneous IG, a therapeutic IG modality with the potential to have a great impact in the quality of life of children with AD and their families.
INTRAVENOUS IMMUNOGLOBULIN FOR ANTIBODY REPLACEMENT THERAPY

Intravenous immunoglobulin (IVIG) is a fractionated blood product made from pooled human plasma. Available in the United States since the early 1980s, it rapidly

Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, The David Geffen School of Medicine at the University of California at Los Angeles, MDCC 12-430, 10833 Le Conte Avenue, Los Angeles, CA 900951752, USA * Corresponding author. E-mail address: tchatila@mednet.ucla.edu (T.A. Chatila). Immunol Allergy Clin N Am 28 (2008) 833849 doi:10.1016/j.iac.2008.07.001 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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substituted the use of intramuscular preparations as replacement therapy in AD states. Because it is manufactured from plasma from thousands of individuals, IVIG contains a mixture of antibodies against a wide spectrum of infectious pathogens. The concentration of antibodies against hepatitis B, diphtheria, measles, tetanus, and polio in the final product must comply with Food and Drug Administration requirements. Titers against other pathogens, including those that more frequently affect patients with AD, such as Streptococcus pneumonia and Haemophilus influenzae subtype B, are presently not regulated by the FDA. These titers can vary significantly among different products and even from batch to batch.6,7 To comply with World Health Organization and FDA guidelines, more than 90% protein content in commercial IVIG should be monomeric IgG with a distribution of IgG subclasses close to that in normal plasma.8,9 Traces of IgM and IgA are present in all products, but the content of the latter can vary significantly between manufacturers depending on the method of IgG purification followed. Other immunomodulatory proteins, such as cytokines, soluble CD4 and CD8 and CD40, and HLA molecules are also present in varying amounts.1,10 The risk of transmission of infectious pathogens by this blood-derived product is minimized by the careful selection of donors, plasma antibody screening, and various procedures of viral inactivation. Since the early 1990s the distinction between IVIG products has increased because of refinements in manufacturing.11 Most of these products have proved to be efficacious in the treatment of AD when compared with historical untreated controls or patients treated with intramuscular IG. The methods of purification, viral inactivation, and the addition of stabilizers vary between different manufacturers and can affect the clinical performance of the different products. Physicians need to be aware of these differences because that could influence their decision in selecting the appropriate product for each individual patient. Further, no one IVIG product currently on the market has approval for all of the FDA-sanctioned indications. There are notably few studies comparing side by side the efficacy of different IVIG products.12 In one such study, patients treated with an IVIG product prepared with a less harsh method of viral inactivation had fewer infections that those who received a solvent-detergent treated IVIG.13 Differences in efficacy between IVIG preparations have also been reported in children with Kawasaki disease.14 Production methods not only can affect efficacy but also tolerability. High sodium and sucrose-containing products, for instance, may be contraindicated in patients with marginal cardiac or renal function. This is also an important consideration in neonates and infants. Reduced blood volumes and immature renal function puts this population particularly at risk of developing electrolytic imbalances or volume overload. For these patients, IVIG products with a higher protein concentration, low osmolarity, and neutral pH constitute the best option. IVIG with products with reduced IgA content may be preferred in patients with IgA deficiency who are still able to produce antibodies of IgE or IgG isotype, because these patients are at risk of developing anaphylactic-type reactions when they receive IgA containing blood products.15
IMMUNOGLOBULIN REPLACEMENT IN CHILDREN

In general, IG replacement therapy is indicated for patients with primary or secondary AD only if they have recurrent or severe infections and defective antibody production. The efficacy of IVIG in this setting is primarily related to the well-known attributes of IgG antibodies to neutralize bacterial toxins, superantigens, and viruses; activate complement; and promote phagocytosis and antibody-mediated cytotoxicity.

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Additional benefits are probably drawn from the less well-characterized anti-inflammatory and immunomodulatory properties of IVIG.1,10 In AD disorders, the hosts ability to mount a protective antibody response against microbial pathogens is markedly impaired. Conceptually, AD can be divided into two groups: the hypogammaglobulinemias, in which deficits in antibody synthesis result in decreased levels of IGs, and the functional antibody defects in which the serum IGs are within the normal range but where the production of antigen-specific responses is defective.
HYPOGAMMAGLOBULINEMIA

Because of the substantial physiologic variation in the concentration of serum IGs in first few years of life, the correct interpretation of IG levels in pediatric patients relies on reference to age-matched controls rather than on absolute values. Evaluation of premature babies requires further adjustment according to their gestational age.16 In general terms, a child with serum IgG levels of less than 2 SD below the mean for age is considered to be hypogammaglobulinemic.17 The levels of the other isotypes (IgA and IgM) usually, but not always, correlate with those of IgG, which is the most abundant serum IG. Although decreased IgG values do not necessarily herald a primary immunodeficiency, the finding of hypogammaglobulinemia in a young patient warrants further investigation. Low IGs in children can result from multiple causes, many of which are unrelated to a primary immunodeficiency (Box 1). In a recent retrospective study from the Childrens Hospital of Philadelphia, about half of the cases of hypogammaglobulinemia were caused by a pre-existing condition known to be accompanied by decreased IG.18 In those in which the IG levels were obtained as part of a diagnostic work-up, only 50% were found to have an immunodeficiency.
PRIMARY IMMUNODEFICIENCIES

The first and foremost indication of IG replacement is to decrease the infections in patients with hypogammaglobulinemia and impaired antibody responses. The prototypical diseases in this group are the agammaglobulinemias: X-linked or autosomal recessive.19 The diagnosis of this condition is usually made in the second or third year of life in a child with a history of recurrent infection, profoundly decreased IGs, and extremely low or absent B cells. In these young patients, early institution of IG therapy can be life-saving. Marked hypogammaglobulinemia across the three isotypes with conserved B cells numbers suggests the diagnosis of common variable immunodeficiency (CVI), whereas decrease in IgG and IgA with normal to elevated IgM is the hallmark of the hyper-IgM syndrome.2022 Children with CVI or hyper-IgM syndrome have a severe impairment in antibody responses and, like agammaglobulinemic patients, usually suffer from recurrent sinopulmonary infections that can be ameliorated by the regular IG infusions. IG replacement is also indicated in infants with severe combined immunodeficiency awaiting transplant and in those in which B-cell function is not restored following transplantation. IgG subclass deficiency rarely results in marked hypogammaglobulinemia. Immunologists commonly request this determination in a child with recurrent infections and normal levels of total IgG.23 In the absence of impaired antibody responses, the significance of a depressed level of any of the IG subclasses is unclear and IG replacement is not indicated.

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Box 1 Causes of hypogammalglobulinemia in children Decreased production Primary antibody defects Transient hypogammaglobulinemia of infancyc X-linked agammaglobulinemiaa Autosomal-recessive agammaglobulinemiaa Hyper-IgM syndromea Common variable immunodeficiencya Ataxia-telangiectasiaa Severe combined immunodeficiencya Prematurityb Malignancyc Posttransplant (solid organ, bone marrow transplant)b Chemotherapyc Drugs Increased loss Congenital heart disease Nephrotic syndromec Intestinal lymphangiectasia Burns Severe atopic dermatitisc Increased catabolism FcRN mutations Myotonic dystrophy Sepsis
a b c

IVIG customarily recommended. Recommended in selected cases. IVIG rarely indicated.

Transient hypogammaglobulinemia of infancy is the most common cause of symptomatic hypogammaglobulinemia in children under the age of 2.24 This diagnosis can only be made in retrospect when the childs IG level reaches age-appropriate levels. Transient hypogammaglobulinemia of infancy follows a benign course, although a few of the young children originally diagnosed with transient hypogammaglobulinemia of infancy develop a more permanent defect.25,26 Most patients with transient hypogammaglobulinemia of infancy do well with appropriate antibiotic management but a few may require short-term IVIG support. The benefits of IVIG in these young patients should be balanced against the possibility of interfering with the normal maturation of the immune system, because at least in vitro, IVIG suppresses both T- and B-cell responses.3,27 For those who go on IVIG, periodic re-evaluation of their immune function is imperative.

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SECONDARY HYPOGAMMAGLOBULINEMIAS Protein-Losing Enteropathy

Protein-losing enteropathy is a condition characterized by severe loss of serum protein into the intestine. Hypogammaglobulinemia can occur in this setting, often associated with severe hypoalbuminemia and edema. A number of conditions have been associated with protein-losing enteropathy. In children, gastrointestinal disorders and congenital heart disease are the leading causes.28,29 Protein-losing enteropathy is a known complication of the Fontan circulation and in other cardiac disorders where an impaired mesenteric circulation results in an ischemic insult of the gastrointestinal mucosa and enteral protein loss.28 Impairment of the lymphatic drainage of the gastrointestinal tract can also lead to protein-losing enteropathy.30 In addition to hypogammaglobulinemia, patients with intestinal lymphangiectasia, also can present with T-cell lymphopenia of varying degrees, rising the suspicion of a combined primary immunodeficiency diseases (PID). IgG levels in protein-losing enteropathy are usually moderately decreased, but they can be very low. Even under these circumstances, IG replacement is not indicated because there is no evidence that infections in patients with protein-losing enteropathy occur at a higher rate or are more severe than in comparable patients with similar comorbidities. It can be argued that, in the face of ongoing protein losses, IG administration is futile. Correction of the underlying disorder usually results in normalization of the IG levels.
Nephrotic Syndrome

A low level of serum IgG with normal or increased IgM is a common finding in children with steroid-sensitive nephrotic syndrome in relapse and in remission.31 Originally presumed to be secondary to urinary protein loss, the hypogammaglobulinemia of steroid-sensitive nephrotic syndrome is now thought to result from complex immune mechanisms intrinsic to the pathogenesis of this disease. A recent study of 44 children with steroid-sensitive nephrotic syndrome showed that the IgG subclass distribution varies depending on the stage of the disease, leading to the suggestion that the preferential loss of certain IgG subclasses may underlie the unusual susceptibility of patients to pneumococcal infections.32 Although functional antibody defects may be a feature of steroid-sensitive nephrotic syndrome, there is no evidence that IG replacement is useful in this condition and it should not be recommended.
Medications

Several classes of medications can lead to secondary hypogammaglobulinemia.33 These include glucocorticoids and other immunosuppressants, chemotherapeutic agents, and anticonvulsants. In most of these cases, the hypogammaglobulinemia is mild and of no clinical significance. IG replacement is not indicated. Discontinuation or substitution by an alternative drug should be considered in the rare instances where IG levels are substantially reduced or if the patient develops unusual or recurrent infections.
Hypogammaglobulinemia Caused by Increased IgG Catabolism

Although generalized hypercatabolic states (eg, infection) are often accompanied by quantitative or qualitative defects in IG production, decreased levels of serum IgG can also result from primary disorders of IG degradation or turnover. Hypogammaglobulinemia is a feature of familial hypercatabolic hypoproteinemia, which is caused by mutations in the b2-microglobulin gene,34 a component of the neonatal Fc receptor (FcRN), which is critically involved in serum IgG homeostasis.35

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Although the mechanism is still unclear, accelerated IgG catabolism is also thought to be behind the hypogammaglobulinemia observed in some patients affected with myotonic dystrophy.36 Interestingly, the gene associated with muscular dystrophy is upstream of the gene encoding the alpha chain of FcRn on chromosome 19, and it has been suggested that there might be a direct or indirect influence on the expression of FcRN and consequently in the catabolic rate of IGs.37 Although the levels of IgG in patients with myotonic dystrophy occasionally are in the range observed in primary immunodeficiency, for the most part they do not suffer from recurrent infections and rarely warrant IG support.
FUNCTIONAL ANTIBODY DEFECTS Primary Specific Antibody Defects

Children who have recurrent sinopulmonary infections with encapsulated bacteria, normal or near normal IgG levels, and impaired antibody responses may pose a diagnostic challenge. Some of these children have additional features that suggest a CVI phenotype and the presumption is that eventually the total IG levels will fall. Others never meet criteria for CVI and their antibody defects remain discrete, leading to the diagnosis of specific antibody deficiency (SAD). The impaired response against polysaccharide antigens is the best characterized feature of SAD.38 More recently, Alachkar and colleagues39,40 showed that children and adults with SAD have decreased numbers of switched memory B cells, which have been argued to play a cardinal role in the protection against encapsulated bacteria. The current view is that IG replacement in SAD should only be considered in the face of recurrent pyogenic infections poorly controlled with antibiotic therapy. In children with SAD who are started on IVIG, the recommendation is to re-evaluate them after a year. If antibody responses improve and infections do not recur, therapy should be discontinued. Impaired polysaccharide responses are found in about one third of patients with DiGeorge syndrome, which is primarily considered a T-cell defect. These patients seldom warrant IVIG administration. Variable defects in antibody production have been reported in a number of complex immunodeficiencies, such as the hyperimmunoglobulinemia E syndrome, Wiskott-Aldrich syndrome, and X-linked proliferative disease.4143 The efficacy of IVIG therapy in these rare disorders is mostly anecdotal but IG supportive therapy is routinely offered to these children in some centers.16
HIV Infection

Profound abnormalities in cellular and humoral immunity are the hallmark of HIV infection. Despite normal or even elevated levels of total serum IGG, children infected with HIV often have impaired antibody responses and suffer from recurrent infections with common pyogenic bacteria, such as S pneumonia and H influenzae. This is in contrast to adults, where opportunistic infections are the major concern. IVIG therapy is now part of the standard of care of pediatric HIV patients, this being one of the six FDAapproved indications for the drug.4 This indication followed the findings from two large randomized, placebo-controlled trials conducted in the early 1990s that demonstrated the benefits of IVIG infusions (400 mg/kg/4weeks) in reducing the number of serious bacterial infections in HIV-infected children.44,45 The advent of more effective antiretroviral therapies, such as highly active retroviral therapy may, however, change this prospect. In a recent study of 15 HIV-infected children by Grisaru-Soen and colleagues46 short-term (<3 months) withdrawal of IVIG was not associated with a significant increase in incidence of infections or a decline in immunologic function.

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Neonatal Sepsis

Neonates are a population at high risk for disseminated infection because of the relative immaturity of their host defense mechanisms.16 In terms of humoral immunity, maternal IgG can offer considerable protection but the infants antibody responses to newly encountered antigens are either delayed (proteins) or absent (polysaccharides). The poor opsonic capacity of neonatal serum leads to inefficient phagocytosis and bacterial killing, These latter abnormalities are even more pronounced in premature babies whose IG levels are markedly lower than those in infants born at term. These observations have provided the rationale for the use of IVIG to improve the outcome of neonatal sepsis. A number of studies have addressed the efficacy of IVIG in the management of neonatal infections. An earlier meta-analysis of trials found significant reduction in the mortality of neonatal sepsis when IVIG was added to conventional therapies.47 In contrast, administration of IVIG seems to be only marginally beneficial for preventing neonatal sepsis and is probably not justified.48
Sepsis in Pediatric Patients

In septic syndromes, the increased demands and the hypercatabolic state often lead to functional antibody deficits that could be partially corrected with IVIG infusions. Indeed, adjuvant therapy with IVIG decreases mortality by more than 30% in adult and in pediatric patients with bacterial sepsis or septic shock as demonstrated by meta-analysis of eight trials involving 492 patients.49 Using slightly different selection parameters, another group reported similar conclusions.50 Of note, IVIG products with high IgM content (not available in the United States) seemed to be superior in this setting, likely because of the increased capacity of pentameric IgM to activate complement and to opsonize gram-negative bacteria.51 Despite this promising evidence, at the present time IG replacement is by no means customary in the treatment of microbial sepsis. Further studies are required to delineate the precise indications, timing, dosage, and IVIG in the management of this disorder.
DOSAGE AND ADMINISTRATION

The primary goal of IG replacement is to reduce the incidence and the severity of infections in patients with AD. Although the efficacy of IG therapy was apparent from the very first clinical trials, the optimal dose to achieve this goal is still a matter of investigation.5254 A number of studies established the superiority of higher IVIG doses (ie, 400600 mg/kg versus 100200 mg/kg every 34 weeks) in reducing the rate of infections, decreasing hospitalization and antibiotic usage, and improving pulmonary outcomes in patients with primary hypogammaglobulinemia.5558 On the basis of these observations, the standard recommended IG replacement dose for children with AD is 100 mg/kg/wk. Doubling this standard dose may further decrease the number of bacterial and viral infections and should be considered in selected patients as recently proposed by Eijkhout and colleagues59 In this double-blind, randomized, crossover study of 43 patients with AD, 18 of whom were children, doubling the standard dose of IVIG significantly reduced the number and duration of infections. These findings suggest that, in selected patients, higher doses of IVIG associated with increased trough levels decrease long-term complications, especially pulmonary ones. For ease and convenience, when the intravenous route is chosen, the infusions are administered every 3 to 4 weeks. Patients with severe hypogammaglobulinemia (<100 mg/dL) may benefit from a total loading dose of 800 mg/kg given

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in two separate doses a few days apart, followed by monthly injections of 400 to 500 mg/kg.4,16 The average half-life of IgG is 21 days, but IgG metabolism shows significant variations among individuals.60 Active infection, endocrine disorders, and autoimmunity have all been associated with increased IgG catabolism.61 These comorbidities, which could potentially reduce the effective dose of replacement IG, are not unusual in patients with PID. Genetic factors can also play a significant role, as illustrated by the higher catabolism of IgG in patients with mutations in the b2-microglobulin chain of the FcRn.34 It is preferable to assess the adequacy of IG replacement in terms of the residual or trough levels of serum IgG rather than on the absolute dose infused. In general, serum IgG troughs of 500 to 600 mg/dL are effective in preventing acute bacterial infections in hypogammaglobulinemic patients. At replacement doses of 500 mg/kg/mo, these levels are usually attained after the sixth infusion (or about six half-lives), once redistribution to the tissues is complete and a steady state is reached.60 Residual serum IgG should be monitored every 2 months until steady state is reached and every 6 months thereafter. In children, periodic dose adjustments are required during periods of accelerated growth but excessive monitoring of IG levels should be avoided. Higher residual IG levels (>800 mg/dL) may be indicated in selected patients with protracted sinus infections or progressive lung damage.4,57 In children with mild to moderate decreases in serum IG (CVI) or in those with functional antibody deficits and normal levels of IGs (SAD), trough levels are more difficult to interpret given that these patients retain some antibody synthetic capabilities.17,62 Some immunologists aim for trough levels of 300 mg/dL higher than the preinfusion levels, whereas others favor troughs in the midrange of the normal for age. Dosing can be more complex, but a starting dose of 400 mg/kg/mo is generally acceptable. In some patients, increasing IG doses may be offset by concomitant enhancement IgG catabolism.60 Increasing the dose does not necessarily raise residual levels of IgG.

ADVERSE REACTIONS

Although IG therapy is generally considered safe, adverse reactions associated with IVIG administration are not uncommon (Box 2). Because most adverse reactions occur in the first few infusions, it is advisable to initiate IG therapy in a hospital setting and under the supervision of a physician experienced in this type of treatment. In that way, adjustments in dosage, type of product, and rate of infusion can be made to ensure optimal tolerability. The reported frequency of IVIG-associated adverse reactions ranges between 2% and 25% of all infusions, depending in the particular disease or patient population studied.63,64 At replacement doses in patients with AD, this frequency is in the order of 10% or less. IVIG-associated reactions tend to be mild to moderate in nature and, as a rule, occur during the first few infusions of the product. In this setting, children are not more likely to experience IVIG-associated adverse reactions than adults. Common symptoms, such as flushing, headaches, and malaise, tend to subside in subsequent administrations. A common practice in many centers is to premedicate patients with acetaminophen and antihistamines with the aim of minimizing these type of reactions. Often, slowing the rate of infusion suffices to abate the symptoms. Because each IVIG product potentially has unique safety and tolerability profiles, it is not uncommon to find that patients who react to one IVIG product tolerate the infusion with no problems when switched to another brand.

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Box 2 Adverse reactions associated with IVIG therapy Mild to moderate Flushinga Chillsa Fevera Headachea Back pain Chest pain Bronchospasm Nausea Myalgiaa Aseptic meningitis Transaminitis Increase creatinine Severe Renal failure Convulsions Thrombosis and stroke Pulmonary edema Hemolysis Anaphylaxis
a

IVIG customarily recommended.

The pathogenesis of IG-associated adverse reactions is variable and depends on the type of product, the amount and the rate of infusion, and the clinical characteristics of the patients. High-dose infusions, for instance, may induce to the formation of IG aggregates or immune complexes that potentially can prompt a generalized inflammatory response. A similar mechanism may be in patients with active infection, which is considered a relative contraindication for IVIG infusion. Severe adverse reactions, such as strokes, acute lung injury, kidney failure, anaphylaxis, and even death, have all been reported in association with IVIG therapy.6568 Fortunately these are very rare events and tend to occur in patients receiving high-dose, repeated infusions for disorders other than AD.63,64 IVIG is a human bloodderived product and, as such, its administration carries the potential risk of transmission of infectious pathogens. Manufacturing techniques now include a multipronged strategy to reduce the risk of potential infections, but in the past there have been a few instances in which this complication has been documented.69 Notably, in the mid-1990s there were several reports of transmission of hepatitis C through IVIG infusions. Most of these cases were patients with PID, some were children.70 Infectious lots were traced to a single manufacturer whose strategy had been to exclude donors positive for hepatitis C antibodies. No episodes of viral transmission caused by IVIG products have been reported after the institution of dedicated viral inactivation methods.

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SUBCUTANEOUS IMMUNOGLOBULIN

Although IVIG clearly improves the quality of life for children with AD, there remain drawbacks to its use. Venous access, in particular, is a serious and potentially lifethreatening concern for chronically ill children, including those with immune deficiencies. IVIG infusion requires newly obtaining venous access on a monthly basis in children. This causes some psychologic distress and pain, and establishment of venous access tends to become more difficult over time, placing the patient and risk should resuscitation be required, and potentially compromising the ability to deliver immune globulin. On occasions, indwelling permanent central catheters are recommended to facilitate the infusion. Such an intervention places an already immunedeficient child at even higher risk for sepsis, thrombosis, arrhythmias, and emboli. The impact of this on the antibody-deficient child should not be underestimated. An alternative exists using clysis, an older method of fluid delivery by subcutaneous infusion. Although clysis is clearly inferior to intravenous infusion for saline resuscitation, it is adequate for IG infusion and evades many of the issues that plague intravenous administration of IG. In a typical subcutaneous infusion of IG, a more concentrated preparation of IVIG is delivered by a catheter and small volume infusion pump into the subcutaneous tissue of the abdomen, thigh, or arm. The antibody solution is gradually absorbed from the subcutaneous tissue by lymphatics and is returned to the circulation by normal lymphatic pathways. This results in more stable levels of IgG over time, limits the fluid load imposed on the patient, and avoids the requirement for obtaining venous access. Although the FDA only recently approved the first formulation for subcutaneous infusion in the United States (Vivaglobin), subcutaneous infusion of immune globulin (SCIG) has been in use since the 1970s and was in widespread use in Europe for many years before United States approval.7182 In general, SCIG is at least equivalent to IVIG in reduction of infections and outcomes, with improved quality of life for patients and substantially reduced cost.76,83,84 SCIG may result in slightly higher trough levels of IgG, probably because of the increased frequency of infusion.79 Although the number of infections is generally the same between SCIG and IVIG, some studies have shown improved outcomes over time and in bone marrow transplant patients that correlated with higher trough levels, suggesting some benefit to higher steady-state IgG levels.59,8587 Other advantages to SCIG is the more limited fluid load and no association with renal failure, a concern for sucrose-containing intravenous preparations. There are limitations to this procedure. Principally, the volume of fluid that can be delivered subcutaneously is limited, requiring the concentration of the IG preparation and potentially requiring infusion in multiple sites. In addition, because of the volume limitation, the infusion must be given weekly, rather than on a monthly basis. Despite the volume limitations, subcutaneous infusion has even been used successfully for a dermatomyositis patient who did not tolerate intravenous administration.88 The primary adverse events are local site reactions, including redness, swelling, and pain. Although these are almost universal at the start (91%), as infusions continue these become less problematic and seldom require return to intravenous infusion.77 Because subcutaneous access requires limited technical skill, parents and even the children themselves can deliver the infusion without the need for nursing services or being logistically dependent on an infusion center. Loss of work or school time is also not an issue for patients receiving SCIG. Although SCIG has clear advantages over IVIG, for pediatric use the increased number of needle sticks is a concern. Although it is easier to obtain access, the number of needle exposures is increased fourfold because of the weekly infusion. This has been

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a problem for some children with severe needle fears. A properly done subcutaneous puncture causes trivial pain and the principal problem that must be addressed in children is avoiding the negative stigma associated with the needle. Ideally, this problem should be managed from the beginning with careful and graded exposure to the infusion apparatus. Anesthetic creams should be used for the first few infusions to eliminate any possible pain associated with puncture. Other strategies are also being investigated to reduce the number of infusions necessary for subcutaneous use of immune globulin. For example, it has already been demonstrated that similar results can be obtained by infusing once every 2 weeks using twice the dose. This can usually be tolerated, although a greater number of sites are needed to accommodate the increased volume.89 Furthermore, a version of 10% IVIG solution (Gammagard or Kiovig) modified for subcutaneous infusion is currently in phase III trials. This preparation has a version of hyaluronidase included to improve diffusion through subcutaneous tissue, allowing a greater volume to be delivered. This permits the infusion to be delivered subcutaneously once per month with similar trough levels and infectious outcomes.90,91 It is not clear whether the same advantage of higher trough levels and more stable steady-state levels can be expected from these alternative preparations. Despite the concern by providers and parents about increased exposure to needle sticks, children tolerate the procedure well and most children and families prefer subcutaneous infusion to intravenous infusion.92 The savings to the family and society are considerable, with SCIG infusions saving $10,100 per patient-year over intravenous infusion in 1997 in a study in Sweden.76 Similar impacts on quality of life were also found in a North American study.93 SCIG also seems to be safe in pregnancy. Although it carries a pregnancy class C rating from the FDA, at least 12 pregnant women have received SCIG without any evident harm to the pregnancy.94,95 Patients with mild bleeding disorders also can tolerate therapy.96 IgA-deficient patients, who are at risk for anaphylaxis caused by contaminating IgA in IVIG, can be tolerized to IgA using subcutaneous infusion.97,98 Although patients who have had severe reactions to IVIG can still have severe reactions to SCIG, these reactions are less common and many patients who do not tolerate IVIG may tolerate SCIG.99,100

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1. Jolles S, Sewell WA, Misbah SA. Clinical uses of intravenous immunoglobulin. Clin Exp Immunol 2005;142:111. 2. Mahadevia PJ. The pocketbook: pharmacoeconomic issues related to intravenous immunoglobulin therapy. Pharmacotherapy 2005;25:94S100S. 3. Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol 2008;26:51333. 4. Orange JS, Hossny EM, Weiler CR, et al. 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. J Allergy Clin Immunol 2006;117:S52553. 5. Clynes R. Protective mechanisms of IVIG. Curr Opin Immunol 2007;19:64651. 6. Givner LB. Human immunoglobulins for intravenous use: comparison of available preparations for group B streptococcal antibody levels, opsonic activity, and efficacy in animal models. Pediatrics 1990;86:95562. 7. Lamari F, Anastassiou ED, Tsegenidis T, et al. An enzyme immunoassay to determine the levels of specific antibodies toward bacterial surface antigens in human

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26. Dorsey MJ, Orange JS. Impaired specific antibody response and increased B-cell population in transient hypogammaglobulinemia of infancy. Ann Allergy Asthma Immunol 2006;97:5905. 27. Takei S, Arora YK, Walker SM. Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens [see comment]. J Clin Invest 1993;91:6027. 28. Driscoll DJ. Long-term results of the Fontan operation. Pediatr Cardiol 2007;28: 43842. 29. Chehade M, Magid MS, Mofidi S, et al. Allergic eosinophilic gastroenteritis with protein-losing enteropathy: intestinal pathology, clinical course, and long-term follow-up. J Pediatr Gastroenterol Nutr 2006;42:51621. 30. Radhakrishnan K, Rockson SG. The clinical spectrum of lymphatic disease. Ann N Y Acad Sci 2008;1131:15584. 31. Schnaper HW. The immune system in minimal change nephrotic syndrome. Pediatr Nephrol 1989;3:10110. 32. Kemper MJ, Altrogge H, Ganschow R, et al. Serum levels of immunoglobulins and IgG subclasses in steroid sensitive nephrotic syndrome. Pediatr Nephrol 2002;17:4137. 33. Jaffe E, Lejtenyi C, Noya F, et al. Secondary Hypogammaglobulinemia. Immunol Allergy Clin North Am 2001;21:14163. 34. Wani MA, Haynes LD, Kim J, et al. Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proc Natl Acad Sci U S A 2006;103:50849. 35. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007;7:71525. 36. Larsen B, Johnson G, van Loghem E, et al. Immunoglobulin concentration and Gm allotypes in a family with thirty-three cases of myotonic dystrophy. Clin Genet 1980;18:139. 37. Pan Q, Hammarstrom L. Molecular basis of IgG subclass deficiency. Immunol Rev 2000;178:99110. 38. Paris K, Sorensen RU. Assessment and clinical interpretation of polysaccharide antibody responses. Ann Allergy Asthma Immunol 2007;99:4624. 39. Alachkar H, Taubenheim N, Haeney MR, et al. Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency. Clin Immunol 2006;120:3108. 40. Carsetti R, Rosado MM, Wardmann H. Peripheral development of B cells in mouse and man. Immunol Rev 2004;197:17991. 41. Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007;357:160819. 42. Nichols KE, Ma CS, Cannons JL, et al. Molecular and cellular pathogenesis of X-linked lymphoproliferative disease. Immunol Rev 2005;203:18099. 43. Ochs HD, Slichter SJ, Harker LA, et al. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets. Blood 1980;55:24352. 44. Spector SA, Gelber RD, McGrath N, et al. A controlled trial of intravenous immune globulin for the prevention of serious bacterial infections in children receiving zidovudine for advanced human immunodeficiency virus infection. Pediatric AIDS Clinical Trials Group. N Engl J Med 1994;331:11817. 45. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. The National

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Institute of Child Health and Human Developments Intravenous Immunoglobulin Study Group. N Engl J Med 1991;325:7380. Grisaru-Soen G, Lau W, Arneson C, et al. Randomized controlled trial of shortterm withdrawal of I.V. immunoglobulin therapy for selected children with human immunodeficiency virus infection. Pediatr Int 2007;49:9727. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database Syst Rev 2004: CD001239. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database Syst Rev 2004: CD000361. Kreymann KG, de Heer G, Nierhaus A, et al. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med 2007;35: 267785. Laupland KB, Kirkpatrick AW, Delaney A. Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med 2007;35:268692. Trautmann M, Held TK, Susa M, et al. Bacterial lipopolysaccharide (LPS)specific antibodies in commercial human immunoglobulin preparations: superior antibody content of an IgM-enriched product. Clin Exp Immunol 1998;111:8190. Cunningham-Rundles C, Siegal FP, Smithwick EM, et al. Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease. Ann Intern Med 1984;101:4359. Eibl MM, Cairns L, Rosen FS. Safety and efficacy of a monomeric, functionally intact intravenous IgG preparation in patients with primary immunodeficiency syndromes. Clin Immunol Immunopathol 1984;31:15160. Nolte MT, Pirofsky B, Gerritz GA, et al. Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol 1979;36:23743. Liese JG, Wintergerst U, Tympner KD, et al. High- vs low-dose immunoglobulin therapy in the long-term treatment of X-linked agammaglobulinemia. Am J Dis Child 1992;146:3359. Quartier P, Debre M, De Blic J, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr 1999;134:58996. Roifman CM, Gelfand EW. Replacement therapy with high dose intravenous gamma-globulin improves chronic sinopulmonary disease in patients with hypogammaglobulinemia. Pediatr Infect Dis J 1988;7:S926. Roifman CM, Levison H, Gelfand EW. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet 1987;1:10757. Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. 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. Ann Intern Med 2001;135:16574. Schiff RI, Rudd C. Alterations in the half-life and clearance of IgG during therapy with intravenous gamma-globulin in 16 patients with severe primary humoral immunodeficiency. J Clin Immunol 1986;6:25664. Blaese RM, Strober W, Levy AL, et al. Hypercatabolism of IgG, IgA, IgM, and albumin in the Wiskott-Aldrich syndrome: a unique disorder of serum protein metabolism. J Clin Invest 1971;50:23318.

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62. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 2002;109:10014. 63. Ballow M. Safety of IGIV therapy and infusion-related adverse events. Immunol Res 2007;38:12232. 64. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfus Med Rev 2003;17:24151. 65. Ahsan N. Intravenous immunoglobulin induced-nephropathy: a complication of IVIG therapy. J Nephrol 1998;11:15761. 66. Burks AW, Sampson HA, Buckley RH. Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia: detection of IgE antibodies to IgA. N Engl J Med 1986;314:5604. 67. Hamrock DJ. Adverse events associated with intravenous immunoglobulin therapy. Int Immunopharmacol 2006;6:53542. 68. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994;121:25962. 69. Schleis TG. The process: new methods of purification and viral safety. Pharmacotherapy 2005;25:73S7S. 70. Bjoro K, Froland SS, Yun Z, et al. Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin. N Engl J Med 1994;331:160711. 71. Abrahamsen TG, Sandersen H, Bustnes A. Home therapy with subcutaneous immunoglobulin infusions in children with congenital immunodeficiencies. Pediatrics 1996;98:112731. 72. Alyanakian MA, Bernatowska E, Scherrmann JM, et al. Pharmacokinetics of total immunoglobulin G and immunoglobulin G subclasses in patients undergoing replacement therapy for primary immunodeficiency syndromes. Vox Sang 2003;84:18892. 73. Berger M, Cupps TR, Fauci AS. Immunoglobulin replacement therapy by slow subcutaneous infusion. Ann Intern Med 1980;93:556. 74. Bjorkander J, Wadsworth C, Hanson LA. 1040 prophylactic infusions with an unmodified intravenous immunoglobulin product causing few sideeffects in patients with antibody deficiency syndromes. Infection 1985; 13:10210. 75. Chapel HM, Spickett GP, Ericson D, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 2000;20:94100. 76. Gardulf A, Andersen V, Bjorkander J, et al. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 1995;345:3659. 77. Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies: a prospective, multi-national study. J Clin Immunol 2006; 26:17785. 78. Gaspar J, Gerritsen B, Jones A. Immunoglobulin replacement treatment by rapid subcutaneous infusion. Arch Dis Child 1998;79:48. 79. Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol 2006;26:26573. 80. Remvig L, Andersen V, Hansen NE, et al. Prophylactic effect of self-administered pump-driven subcutaneous IgG infusion in patients with antibody deficiency: a

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triple-blind cross-over study comparing P-IgG levels of 3 g l-1 versus 6 g l-1. J Intern Med 1991;229:737. Ugazio AG, Duse M, Re R, et al. Subcutaneous infusion of gammaglobulins in management of agammaglobulinaemia. Lancet 1982;1:226. Waniewski J, Gardulf A, Hammarstrom L. Bioavailability of gamma-globulin after subcutaneous infusions in patients with common variable immunodeficiency. J Clin Immunol 1994;14:907. Gardulf A, Borte M, Ochs HD, et al. Prognostic factors for health-related quality of life in adults and children with primary antibody deficiencies receiving SCIG home therapy. Clin Immunol 2008;126:818. Gardulf A, Nicolay U. Replacement IgG therapy and self-therapy at home improve the health-related quality of life in patients with primary antibody deficiencies. Curr Opin Allergy Clin Immunol 2006;6:43442. Cottler-Fox M, Lynch M, Pickle LW, et al. Some but not all benefits of intravenous immunoglobulin therapy after marrow transplantation appear to correlate with IgG trough levels. Bone Marrow Transplant 1991;8:2733. Leen CL, Yap PL, McClelland DB. Increase of serum immunoglobulin level into the normal range in primary hypogammaglobulinaemia by dosage individualization of intravenous immunoglobulin. Vox Sang 1986;51:27886. Ochs HD, Fischer SH, Wedgwood RJ, et al. Comparison of high-dose and lowdose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases. Am J Med 1984;76:7882. Schleinitz N, Jean E, Benarous L, et al. Subcutaneous immunoglobulin administration: an alternative to intravenous infusion as adjuvant treatment for dermatomyositis? Clin Rheumatol 2008;27:10678. Gustafson R, Gardulf A, Hansen S, et al. Rapid subcutaneous immunoglobulin administration every second week results in high and stable serum immunoglobulin G levels in patients with primary antibody deficiencies. Clin Exp Immunol 2008;152:2749. Bjorkander J, Nikoskelainen J, Leibl H, et al. Prospective open-label study of pharmacokinetics, efficacy and safety of a new 10% liquid intravenous immunoglobulin in patients with hypo- or agammaglobulinemia. Vox Sang 2006;90: 28693. Church JA, Leibl H, Stein MR, et al. Efficacy, safety and tolerability of a new 10% liquid intravenous immune globulin [IGIV 10%] in patients with primary immunodeficiency. J Clin Immunol 2006;26:38895. Fasth A, Nystrom J. Safety and efficacy of subcutaneous human immunoglobulin in children with primary immunodeficiency. Acta Paediatr 2007;96:14748. Nicolay U, Kiessling P, Berger M, et al. Health-related quality of life and treatment satisfaction in North American patients with primary immunodeficiency diseases receiving subcutaneous IgG self-infusions at home. J Clin Immunol 2006; 26:6572. Berger M, Cupps TR, Fauci AS. High-dose immunoglobulin replacement therapy by slow subcutaneous infusion during pregnancy. JAMA 1982;247: 28245. Gardulf A, Andersson E, Lindqvist M, et al. Rapid subcutaneous IgG replacement therapy at home for pregnant immunodeficient women. J Clin Immunol 2001;21:1504. Arora R, Newton TC, Nelson MR. Subcutaneous immunoglobulin therapy in an 11-year-old patient with common variable immunodeficiency and von Willebrand disease. Ann Allergy Asthma Immunol 2007;99:36770.

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97. de Albuquerque Campos R, Sato MN, da Silva Duarte AJ. IgG anti-IgA subclasses in common variable immunodeficiency and association with severe adverse reactions to intravenous immunoglobulin therapy. J Clin Immunol 2000; 20:7782. 98. Sundin U, Nava S, Hammarstrom L. Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy. Clin Exp Immunol 1998;112:3416. 99. Quinti I, Soresina A, Agostini C, et al. Prospective study on CVID patients with adverse reactions to intravenous or subcutaneous IgG administration. J Clin Immunol 2008;28:2637. 100. Stiehm ER, Casillas AM, Finkelstein JZ, et al. Slow subcutaneous human intravenous immunoglobulin in the treatment of antibody immunodeficiency: use of an old method with a new product. J Allergy Clin Immunol 1998;101:8489.

I ntravenous Gammaglobulin Treatment in HIV -1 I nfe c tion

Avi Deener, MDa, Ami Mehra, MDa, Larry Bernstein, MDa, Jenny Shliozberg, MDa, Arye Rubinstein, MD, PhDa,b,*
KEYWORDS  Immunodeficiency  B cells  T cells  Highly active antiretroviral therapy (HAART)  HIV-1  AIDS  Thrombocytopenia  Opportunistic infections

HISTORICAL BACKGROUND OF GAMMAGLOBULIN REPLACEMENT IN HIV/AIDS

In 19781979, children with an unusual clinical and immunologic profile were observed at Albert Einstein College of Medicine.13 These children presented with recurrent bacterial infections; several had multiple septic episodes with the same organism that failed to respond to specific antibodies.1,4 Their clinical presentation appeared typical for a B-cell deficiency such as Brutons agammaglobulinemia. In contrast to parents of children with congenital B-cell deficiencies, parents of these children also presented with immune aberrations, including cell-mediated immunity and B-cell immunity, which suggested that a transmittable infectious agent may be involved. Researchers soon recognized that the childrens B-cell deficiency was unique in its immunologic and histopathologic profile. They had a prominent generalized lymphadenopathy, and their lymph node biopsies revealed a marked proliferation of B cells. They also exhibited a pan-hypergammaglobulinemia that encompassed all three immunoglobulin classes: IgA, IgM, and IgG.13 Despite the hypergammaglobulinemia, they failed to mount specific antibody responses to various antigens.5 Most prominent was their inability to mount specific antibodies to polysaccharide antigens.

This work was supported by Grant No.AI051519 from the National Institutes of Health. a Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 1525 Blondell Avenue, Bronx, NY 10461, USA b Department of Microbiology and Immunology, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 1525 Blondell Avenue, Bronx, NY 10461, USA * Corresponding author. Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 1525 Blondell Avenue, Bronx, NY 10461. E-mail address: rubinste@aecom.yu.edu (A. Rubinstein). Immunol Allergy Clin N Am 28 (2008) 851859 doi:10.1016/j.iac.2008.06.001 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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Treatment of these children, who were later identified as being infected with HIV-1, with intravenous immunoglobulin (IVIG) not only abolished the recurrent bacterial infections 68 but also induced previously unexpected immunomodulatory effects.814 The introduction of antiretroviral therapies had an effect on immune functions in pediatric and adult patients infected with HIV-1, in most instances deviating the need for IVIG.
USE OF INTRAVENOUS GAMMAGLOBULIN IN THE PRE-ANTIRETROVIRAL ERA

The B-cell immune system in children infected with HIV-1 is more compromised than that of adults who have HIV-1. Maturation of the B-cell compartment is physiologically incomplete at birth, and protection against common pathogens is provided by passive transplacental transfer of maternal IgG. Even babies with Brutons agammaglobulinemia usually enjoy an infection-free interval of 6 to 9 months through passive immunity. This is not always the case in infants who are infected with HIV-1. Because humoral (B-cell) and cellular (T-cell) immune defects are noted in pregnant women who are infected with HIV-1, the protection of their infants through passive immunity is incomplete. This finding explains the often earlier onset of bacterial and septic infections in individuals who are infected with HIV-1. The maturation of B cells in infants who are infected with HIV-1 is further compromised by the inadequate interaction provided by dysfunctional T cells and by abnormal thymic epithelium function. Decreased levels of circulating thymulin, a marker of thymic dysplasia, have been noted in infants infected with HIV-1.15 In 1979, our rationale for the introduction of IVIG in children infected with HIV-1 was based on documents of in vivo defective primary and secondary antibody responses to a T-celldependent bacteriophage neoantigen (4X174), tetanus toxoid, and a B-celldependent pneumococcal polysaccharide antigen.5,16 The poor secondary responses to these antigens included abnormal class switches from IgM to IgG.16 Further in vitro evidence of B-cell dysfunction was the poor lymphocyte proliferative response to Pokeweed mitogen and Staphylococcal aureus, a T-cellindependent B-cell mitogen.13 Pokeweed mitogen also failed to induce in vitro B-cell secretion of IgG in the presence of normal T lymphocytes.12 The IVIG regimen used between 1979 and 1982 was the same as that used for patients who had agammaglobulinemia (200300 mg/kg monthly). In 1982, evidence emerged for an associated multitude of immune aberrations, including markedly elevated circulating immune complexes,9,13 elevated serum neopterin levels,10 elevated serum tumor necrosis factor a,11 elevated serum b2-microglobulin,14 isomorphic elevation of serum lactate dehydrogenase,17 and T-cell dysregulation of humoral immunity.12 The IVIG regimen was subsequently modified to address the additional factors. The dose was increased to 300 mg/kg every 2 weeks (instead of every 4 weeks). The following account details the clinical and immune alterations by IVIG in a 10-year follow-up of 112 children aged 9 months to 6 years who were treated by the latter intensified protocol.
Infectious Complications

Only mild upper respiratory infections occurred. No additional episodes of sepsis were noted at 300 mg/kg biweekly as compared with 13 serious bacterial infections in children who received 200 to 300 mg/kg monthly.
Immunomodulatory Effects

Serum IgG levels did not increase over baseline in IVIG-treated patients, whereas a progressive increase in serum IgG was noted in most untreated infants. After IVIG

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treatment there was a statistically significant decrease in b2-microglobulin and lactate dehydrogenase levels. As markers of immune activation, neopterin10 and tumor necrosis factor a also decreased or normalized.11 Circulating immune complexes levels decreased in 77% of patients on the intensified IVIG protocol but in none of 24 untreated patients and in 10 patients who received the monthly IVIG dose of 200 mg/kg.9,13 In children infected with HIV-1, the CD81 T-cell compartment is markedly increased, but these cells are of poor function, as documented by the failure of CD81 T cells to suppress in vitro Pokeweed mitogendriven IgG secretion.12 The reduced Pokeweed mitogendriven IgG secretion normalized in 80% of studied subjects after IVIG treatment. The absent in vitro Concanavalin A generation of suppressor T cells was restored in IVIG-treated patients.12 Statistically significant increases in percentage and absolute T-cell counts were observed in 43% of treated patients. This trend persisted in most patients for up to 10 years until highly active antiretroviral therapy (HAART) was introduced.68 In vitro lymphocyte mitogenic responses to phytohemagglutinin increased transiently in 71% of patients who received IVIG.6 A large National Institute of Child Health and Human Development (NICHD) randomized double-blind placebo controlled multicenter IVIG study on children infected with HIV-1 was conducted 10 years later. This study corroborated most of the earlier findings, although the benefits achieved were not as robust. The IVIG regimen used was different in that 400 mg/kg were administered every 4 weeks.1821 In this trial, children who had a baseline CD41T-cell count of more than 200/mL remained free from serious laboratory-proven and clinical diagnosed bacterial infections.1820 In contrast to our studies with the higher IVIG dose, no statistically significant benefit was noted in children with fewer than 200 CD41T-cells/mL. This difference is probably due to the less intensive IVIG regimen. The NICHD study confirmed the immunomodulatory effect on CD41 T cells with a statistically significant slower decline in CD41 T-cell counts.21 IVIG also was used to treat several autoimmune manifestations, most prominently thrombocytopenia, which is a frequent complication of several conditions, including pediatric HIV-1 infection,22 sepsis,23 and conditions that involve antiplatelet IgG.24 The incidence of thrombocytopenia in children infected with HIV-1 who were on prophylactic IVIG was lower than in untreated patients. Thrombocytopenia, including septic thrombocytopenia, responded promptly with increased platelet counts after high-dose IVIG at 1 g/kg.2224 The numeric platelet responses were not always associated with a favorable clinical outcome, however. In contrast to adults with HIV-1associated thrombocytopenia, children may have antiplatelet antibodies and autoantibody-mediated vasculitis or clotting factor abnormalities.25 As a result, they have more frequent episodes of bleeding and a poorer prognosis.
Intravenous Gammaglobulin in Adults Who Have HIV-1 Infection

Questions have been raised as to whether IVIG plays a role in adults who are infected with HIV-1.26 HIV-1 infected adults may retain their full complement of B cells, including anamnestic antibody responses, for a while because they were formed before their HIV-1 infection. As a result, adults who have HIV-1 infection are less susceptible to infections with common pathogens. HIV-1 can, however, profoundly affect humoral immunity in a subset of infected adults. Polsky and colleagues27 and Selwyn and colleagues28 reported a marked increase in the number of bacterial pneumonias, mainly caused by Staphylococcus pneumoniae and Haemophilus influenza, in adults who have AIDS, most of whom were substance abusers. Janoff and colleagues29

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estimated that the rate of pneumococcal bacteremia among patients who have AIDS was 100-fold higher than in age-matched controls. These findings formed the rationale for use of IVIG in adults. Several uncontrolled clinical trials have not shown conclusive benefits to routine IVIG prophylaxis. There was also no evidence that IVIG delayed progression of HIV-1related disease or had immunomodulatory effects as noted in children who were infected with HIV-1. In a small randomized IVIG trial, Schrappe-Bacher and colleagues30 showed no changes in CD41 cell counts or other clinical and immunologic parameters. These studies should not exclude the use of IVIG for adults who are infected with HIV-1 with recurrent bacterial infections that are not well controlled with antibiotics. In this subset of patients, the use of bacterial vaccines was first studied. Because initial uncontrolled studies suggested an acceptable immunogenicity of polysaccharide vaccines, pneumococcal vaccines were recommended as a standard of care for adults who are infected with HIV-1 in North America and the United Kingdom. Unfortunately, a meta-analysis of prospective randomized pneumococcal vaccine trials did not show efficacy among the subgroup of North American adults infected with HIV-1.31 A second clinical trial with a pneumococcal vaccine was evaluated in Africa, where invasive pneumococcal disease was particularly prevalent in adults who are HIV-1 infected. The study showed not only lack of efficacy but also evidence of vaccine harm,32 probably caused by immune activation. We have shown in an animal model that HIV-1 was enhanced by the capsular polysaccharide of Cryptococcus neoformans.33 Brichachek and colleagues34 noted an increased plasma HIV-1 burden after challenge with a pneumococcal vaccine. We reported transient up-regulation of HIV-1 transcription after a phage FX174 vaccine16 and pneumococcal immunizations. After bacteriophage immunization, a transient decline in CD41 cells was noted. It was recommended that vaccination should preferably be administered only in tandem with antiretroviral therapy. Because it is unclear what level of antibodies is protective in HIV-1 infected patients and the finding that bacterial vaccines may be ineffective or harmful, prophylactic IVIG may be an option in patients with documented recurrent bacterial infections and absent or marginal bacterial vaccine responses. There is evidence for the use of IVIG in adults with autoimmune thrombocytopenia. The incidence of thrombocytopenia in adult patients who have HIV-1 is estimated at 65 per 10,000 persons, whereas the incidence of thrombocytopenia in HIV-1negative patients is estimated at 1.5 per 10,000 individuals.35,36 The introduction of HAART has been effective in mitigating thrombocytopenias, but no studies are available on the incidence of autoimmune thrombocytopenia for patients treated with HAART. The two most common treatments, steroids and splenectomy, remain undesirable for patients who have thrombocytopenia and HIV-1, regardless of whether they are on HAART. In a study by Cai and colleagues,37 the use of steroids was associated with an increased risk of developing Kaposis sarcoma. Splenectomy was associated with an increased susceptibility to infections with encapsulated organisms. In a recent study by Gyongyossy-Issa and colleagues,38 the thrombopoietic responses to IVIG treatment were evaluated in patients who were uninfected with HIV-1 and had immune thrombocytopenic purpura and patients who had HIV-1associated autoimmune thrombocytopenia. The initial response to IVIG in HIV-1 autoimmune patients who had thrombocytopenia was similar to that seen in patients who were not infected with HIV-1. Often-repeated doses were required to maintain an adequate response, however.39 As a result, the question was raised as

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to whether low-dose IVIG is effective. In 13 patients treated with low-dose IVIG (400 mg/kg/wk for 5 weeks), Majluf-Cruz and colleagues40 demonstrated a sustained response 3 months after the end of treatment. Anti-D therapy has been studied in the treatment of HIV-1associated thrombocytopenia as an alternative to IVIG. In a prospective study, 14 Rh1 patients who had HIV-1 received 12 to 25 mg/kg of anti-D IgG intravenously on 2 consecutive days. Nine patients had a rapid and significant increase in their platelet counts. These data suggested that anti-Rh IgG is effective and safe in HIV-1related thrombocytopenic purpura.40 A small, prospective, randomized study by Scaradavou and colleagues41 compared anti-D therapy with IVIG. Nine patients who were Rh1 and had HIV-1 were treated with IVIG or anti-D for 3 months. Patients who were treated with anti-D demonstrated higher mean peak platelet counts and longer duration of response. Anti-D resulted in a mean peak platelet count of 77,000/mL compared with only 29,000/mL after IVIG (P 5 .07). The mean duration of response was significantly longer in patients treated with anti-D (41 days) compared with IVIG (19 days; P 5 .01). This study may support the use of anti-D as first-line therapy in patients who are Rh1 and have HIV-1 and need urgent treatment for thrombocytopenia. In a retrospective study, Lesprit and colleagues42 compared the cost of anti-D therapy to high-dose IVIG. The cost of IVIG per treated episode was $4269, compared with $2716 for anti-D therapy. Overall, based on the evaluation of incidence, treatment patterns, and hospital care required, anti-D therapy was associated with significantly lower costs. Because lower doses of IVIG also were found to be effective, however,40 it remains more cost effective than anti-D therapy. Rheumatic manifestations may develop at any time during the clinical spectrum of HIV-1 infection, but they are usually seen more often in late stages. Various disorders may be seen, particularly Reiters syndrome and undifferentiated spondyloarthropathy. Most patients do well with conventional anti-inflammatory therapy, but some patients require immunosuppressive-cytotoxic therapy. IVIG has not been studied in these situations, except for in cases of polymyositis, in which patients who received high-dose IVIG showed dramatic improvement.43
USE OF INTRAVENOUS GAMMAGLOBULIN IN THE ERA OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPIES

Recent advances with HAART have dramatically reduced mortality and morbidity and prolonged life expectancy. Immune restoration is an important component of HAART. There is an initial increase in CD41 and CD81 T cells and B cells followed by improved in vitro lymphocyte proliferative responses and the return of delayed-type skin hypersensitivity reactions.44 Not all patients demonstrate a substantial T-cell reconstitution, and no controlled studies evaluated the restoration of the functional integrity of the humoral immune responses. Most studies on the restoration of B-cell function or the lack thereof were performed in children with HIV-1 infection and may not reflect the situation in adults. Questions that were raised discussed whether HAART restores the humoral immune system in children who are infected with HIV-1 to function in a relatively normal way; that is, to recognize an antigen, produce antibodies to that antigen, and create and sustain memory B cells for quick production of protective antibodies in the event of re-exposure. One of the first studies that examined this issue was published in 1996. In the face of a measles epidemic in New York City, Arpadi and colleagues45 studied measles antibody titers among children aged 9 to 168

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months who had HIV-1. They correlated measles titers with CD41 cell counts along with other parameters, including age of first measles immunization and the number of immunizations. They found that CD41 T-cell counts had a positive correlation with ones ability to maintain measles antibodies. Among children who had no T-cell immunosuppression, 82% maintained immunity, whereas among the most severely compromised (CD41 T-cell counts % 600/mL) only 53% had positive measles antibody titers. Overall, 72% of previously vaccinated children maintained immunity compared with 95% of healthy children. Treatment with zidovudine at the time of vaccination was significantly associated with the children testing seropositive to measles. Moir and colleagues46 studied the mechanisms by which uncontrolled HIV-1 infection may compromise B-cell function. They showed that in viremic patients (patients who were either on HAART-resistant regimens or were noncompliant with HAART) compared with aviremic patients who had HIV-1, B cells were less responsive to CD41 T cells. This finding was still true when controlling for CD41 T-cell numbers. Their studies showed that this B-cell dysfunction was likely related to B cells inability to up-regulate CD25 (interleukin-2 receptor) in response to appropriate CD41 T-cell signaling in the presence of HIV-1 viremia. Thus, HIV-1 viremia may cause an inherent B-cell dysfunction independent of T-cell function. Bekker and colleagues47 documented that even after immune reconstitution with effective HAART, B-cell memory was not restored to vaccination (MMR) and naturally occurring viral pathogens (VZV, CMV, EBV). The most imperative of B-cell functions providing specific antibodies to previously exposed antigenswas not restored. Overall, 40% of the patients lost immunity to measles, 38% lost immunity to mumps, and 11% lost immunity to rubella. Only 43% maintained immunity to all three pathogens, and 20% lost varicella zoster virus titers after being followed longitudinally on HAART. B-cell reconstitution by HAART was also studied by Rosenblatt and colleagues48 in children aged 4 months to 17 years who were HIV-1 infected and lost their titers to tetanus and then underwent HAART therapy. These children had only mild to moderate impairment in their immune status before enrolling in this study; their percentage of CD41 cells was more than 15% with a median absolute count of 976 cells. After reimmunization with tetanus, most (74%) had a good response 4 weeks later; however, the percentage of patients with a positive titer dropped to 67% at 8 weeks, 53% at 18 weeks, and 38% at 32 weeks. In a study that compared patients who had common variable immune deficiency, patients who underwent splenectomy, and patients who had HIV-1 infection, Hart and colleagues49 reported a decreased response to Pneumovax among individuals who had HIV-1 infection and were on HAART. They showed that this poor response was caused by a relative deficiency in IgM memory B cells. This finding provided an explanation for the increased risk of invasive pneumococcal disease among people who have HIV-1 infection. These data suggested that a segment of patients who have HIV-1 who exhibit poor B-cell functions, respond poorly to bacterial vaccines, and have recurrent bacterial infections may be candidates for prophylactic IVIG treatment. No controlled studies have documented the immunomodulatory effect of IVIG on patients who are infected with HIV-1 and are on HAART; nor have studies examined the effect that IVIG may have on reducing morbidity and mortality. The use of IVIG for autoimmune manifestations on HAART remains controversial and an unchartered field. It plays a role in autoimmune thrombocytopenia for the preHAART era.

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REFERENCES

1. Rubinstein A, Sicklick M, Gupta A, et al. Acquired immunodeficiency with reversed T4/T8 ratios in infants born to promiscuous and drug-addicted mothers. JAMA 1983;249:23459. 2. Rubinstein A. Acquired immunodeficiency syndrome in infants [editorial]. Am J Dis Child 1983;137:8256. 3. Rubinstein A, Bernstein L, Small C. Autoantibodies to AIDS-T cells. Ann N Y Acad Sci 1985;437:5089. 4. Bernstein L, Krieger BZ, Novick B, et al. Bacterial infection in the acquired immunodeficiency syndrome of children. Pediatr Infect Dis 1985;4:4725. 5. Bernstein L, Ochs H, Wedgewood R, et al. Defective humoral immunity in children with AIDS. J Pediatr 1985;107:3527. 6. Rubinstein A, Calvelli T, Rubinstein R. Intravenous gammaglobulin for pediatric HIV-1 infection: effects on infectious complications, circulating immune complexes and CD4 cell decline. Ann N Y Acad Sci 1993;693:1517. 7. Calvelli T, Rubinstein A. Immunodeficiency: pediatric AIDS. In: Rosen FS, editor. Clinical aspects of immunology. 5th edition. Oxford, England: Blackwell Scientific Publication, Ltd; 1993. p. 134168. 8. Calvelli TA, Rubinstein A. Intravenous gamma-globulin in infant acquired immunodeficiency syndrome. Pediatr Infect Dis 1986;5:S2078. 9. Ellaurie M, Calvelli T, Rubinstein A. Human immunodeficiency virus (HIV) circulating immune complexes in infected children. AIDS Res Hum Retroviruses 1990;6:143744. 10. Ellaurie M, Calvelli T, Rubinstein A. Neopterin levels in pediatric HIV infection as predictor of disease activity. Pediatr Infect Dis J 1992;11:2869. 11. Ellaurie M, Rubinstein A. Tumor necrosis factor in pediatric HIV-1 infection. AIDS 1992;6:12658. 12. Gupta A, Novick ME, Rubinstein A. Restoration of suppressor T-cell functions in children with AIDS following intravenous gamma globulin treatment. Am J Dis Child 1986;140:1436. 13. Ellaurie M, Calvelli T, Rubinstein A. Immune complexes in pediatric HIV infection. Am J Dis Child 1990;144:12079. 14. Ellaurie M, Rubinstein A. Beta-2-microglobulin concentrations in pediatric human immunodeficiency virus infection. Pediatr Infect Dis 1990;9:8079. 15. Rubinstein A, Novick BE, Sicklick MJ, et al. Circulating thymulin and thymosin a1 activity in pediatric acquired immunodeficiency ayndrome (in vivo and in vitro studies). J Pediatr 1986;109:4227. 16. Rubinstein A, Mizrachi Y, Bernstein L, et al. Progressive specific immune attrition after primary, secondary and tertiary immunizations with bacteriophage 4X174 in asymptomatic HIV-1 infected patients. AIDS 2000;14:F5562. 17. Silverman B, Rubinstein A. Serum lactate dehydrogenase in adults and children with AIDS and ARC: possible indicator of B cell proliferation and disease activity. Am J Med 1985;78:72836. 18. The NCHD Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic HIV infection. N Engl J Med 1991;325:7380. 19. Mofenson LM, Moye J Jr, Bethel J, et al. Prophylactic intravenous gammaglobulin in HIV-infected children with CD41 counts of 0.20/L or more. JAMA 1992;268:4838. 20. Mofenson LM, Moye J Jr, Korelitz J, et al. Crossover of placebo patients to intravenous immunoglobulin confirms efficacy for prophylaxis of bacterial infections

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22. 23. 24. 25. 26. 27. 28. 29.

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35. 36.

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39.

and reduction of hospitalizations in HIV-infected children. Pediatr Infect Dis J 1994;13:47784. Mofenson LM, Bethel J, Moye J Jr, et al. Effect of intravenous immunoglobulin (IVIG) on CD41 lymphocyte decline in HIV-infected children in a clinical trial of IVIG infection prophylaxis. J Acquir Immune Defic Syndr 1993;6:110313. Ellaurie MD, Shah K, Bernstein LJ, et al. Thrombocytopenia in pediatric AIDS. Pediatrics 1988;82:9058. Burns ER, Lee V, Rubinstein A. Treatment of septic thrombocytopenia with immune globulin. J Clin Immunol 1991;11:3638. Ellaurie M, Burns ER, Rubinstein A. Platelet associated IgG in pediatric HIV infection. Pediatr Hematol Oncol 1991;8:17985. Burns ER, Krieger BZ, Bernstein L, et al. Acquired circulating anticoagulants in pediatric AIDS. Pediatrics 1988;82:7635. Yap PL. Does intravenous immune globulin have a role in HIV-infected patients? Clin Exp Immunol 1994;97(Suppl 1):5967. Polsky B, Gold JWM, Whimbey E, et al. Bacterial pneumonias in patients with AIDS. Ann Intern Med 1986;104:3841. Selwyn PA, Feingold AR, Hartel D, et al. Increased risk of bacterial pneumonias in HIV-infected intravenous drug users without AIDS. AIDS 1988;2:26772. Janoff EN, Breiman RF, Daley CL, et al. Pneumococcal disease during HIV infection: epidemiologic, clinical and immunologic perspectives. Ann Intern Med 1992;117:31424. Schrappe-Bacher M, Rasokat H, Bauer P, et al. High dose intravenous gammaglobulin in HIV-infected adults with AIDS-related complex and Walter Reed 5. Vox Sang 1990;59(Suppl 1):314. Fine MJ, Smith MA, Carson CA, et al. Efficacy of pneumococcal vaccination: a meta-analysis of randomized controlled trials. Arch Intern Med 1994;154: 266677. French N, Nakiyingi J, Carpenter LM, et al. 23 Valent pneumococcal polysaccharide vaccine in HIV-1 infected Ugandan adults: double-blind, randomized and placebo controlled trial. Lancet 2000;355:210611. Pettoello-Mantovani M, Casadevall A, Kollmann TR, et al. Enhancement of HIV-1 infection by the capsular polysaccharide of Cryptococcus neoformans. Lancet 1992;339(8784):21(1)3. Brichachek B, Swindells S, Janoff EN, et al. Increased plasma HIV-1 burden following antigenic challenge with pneumococcal vaccine. J Infect Dis 1996;174: 11919. Morris L, Distenfeld A, Amorosi E, et al. Autoimmune thrombocytopenic purpura in homosexual men. Ann Intern Med 1982;96:7147. Simpson KN, Coughlin CM, Eron J, et al. Idiopathic thrombocytopenia purpura: treatment patterns and an analysis of cost associated with intravenous immunoglobulin and anti-D therapy. Semin Hematol 1998;35(1):5864. Cai J, Zheng T, Lotz M, et al. Glucocorticoids induce Kaposis sarcoma cell proliferation through the regulation of transforming growth factor. Blood 1997;89: 14917. Gyongyossy-Issa MI, Bussel JB, Carter CJ, et al. Comparison of thrombopoiesis during ITP and HIV-ITP and response to intravenous gammaglobulin treatment. Platelets 2003;14(5):26776. Oksenhendler E, Bierling P, Brossard Y, et al. Anti-RH immunoglobulin therapy for human immunodeficiency virusrelated immune thrombocytopenic purpura. Blood 1988;71(5):1499502.

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 40. Majluf-Cruz A, Luna-Castanos G, Huitron S, et al. Usefulness of a low-dose intravenous immunoglobulin regimen for the treatment of thrombocytopenia associated with AIDS. Blood 1993;82(5):141521. 41. Scaradavou A, Cunningham-Rundles S, Ho JL, et al. Superior effect of intravenous anti-D compared with IV gammaglobulin in the treatment of HIVthrombocytopenia: results of a small, randomized prospective comparison. Am J Hematol 2007;82(5):33541.  42. Lesprit P, Pedrono G, Molina JM, et al. ANRS 114-Pneumovac Study Group. Immunological efficacy of a prime-boost pneumococcal vaccination in HIV-infected adults. AIDS 2007;21(18):242534. 43. Viard JP, Vittecog D, Lacroix C, et al. Response of HIV-1 associated polymyositis to intravenous gammaglobulin. Am J Med 1992;92:5801. 44. Smith KY, Valdez H, Landay A, et al. Thymic size and lymphocyte restoration in HIV infected patients following 48 weeks of therapy with zidovudine, lamivudine and ritonavir. J infect Dis 2000;181:1417. 45. Arpadi SM, Markowitz LE, Baughman AL, et al. Measles antibody in vaccinated human immunodeficiency virus type 1-infected children. Pediatrics 1996;97(5): 6537. 46. Moir S, Ogwaro KM, Malaspina A, et al. Perturbations in B cell responsiveness to CD41 T cell help in HIV-infected individuals. Proc Natl Acad Sci USA 2003;10: 605762. 47. Bekker V, Scherpbier H, Pajkrt D, et al. Persistent humoral immune defect in highly active antiretroviral therapy-treated children with HIV-1 infection: loss of specific antibodies against attenuated vaccine strains and natural viral infection. Pediatrics 2006;118(2):e31522. 48. Rosenblatt HM, Song LY, Nachman SA, et al. Tetanus immunity after diphtheria, tetanus toxoids, and acellular pertussis vaccination in children with clinically stable HIV infection. J Allergy Clin Immunol 2005;116:698703. 49. Hart M, Steel A, Clark SA, et al. Loss of discrete memory B cell subsets is associated with impaired immunization responses in HIV-1 infection and may be a risk factor for invasive pneumococcal disease. J Immunol 2007;178:821220.

Economic A ssessment of Different Mo dalities of I mmunoglobulin Replacement Therapy

Stephen K. Membe, MDEa, Chuong Ho, MDa, Karen Cimon, MLTa, Andra Morrison, BSca, Amin Kanani, MD, FRCP(C)b, Chaim M. Roifman, MD, FRCPCc,*
KEYWORDS  Subcutaneous  Intravenous  Cost-effectiveness  Cost-minimization  Immunoglobulin  Immunodeficiency

The most common significant inherited immunodeficiency is characterized by an inadequate production of antibodies. This feature is shared by a variety of genetically and phenotypically distinct disorders such as x-linked agammaglobulinemia, common variable immunodeficiency, or hyper-immunoglobulin M (IgM) syndrome.1 The functional defect in these disorders might be limited to the B cell or T cell compartments or involve both domains of the immune system. The lack of antibodies and thus the failure to respond to vaccinations predisposes these patients to invasive and potentially life-threatening infections. Unable to actively immunize these patients, attempts were made to replace antibodies with those derived from blood of immunocompetent individuals.2,3 Initially only limited quantities of immunoglobulins (Ig) could be delivered through plasma infusions or intramuscular injections.4,5 This treatment was painful and quantitatively inadequate. A major advancement in this field was the introduction of immunoglobulins suitable for intravenous use (IVIg).6 In the early 1980s, IVIg containing reduced IgG aggregates and low concentrations of IgA was introduced.6 IVIg could be administered in large doses which could achieve physiologic serum IgG through levels.79 This in turn dramatically reduced the frequency of infections and improved already existing lung disease.79

Canadian Agency for Drugs and Technologies in Health (CADTH), 600-865 Carling Avenue, Ottawa, ON, Canada K1S 5S8 b St. Pauls Hospital and the University of British Columbia, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6 c The Hospital for Sick Children, Division of Immunology and Allergy, 555 University Avenue, Toronto, ON, Canada M5G 1X8 * Corresponding author. E-mail address: croifman@sickkids.ca (C.M. Roifman). Immunol Allergy Clin N Am 28 (2008) 861874 doi:10.1016/j.iac.2008.06.008 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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The intravenous (IV) route is presently the most common route of administration for Ig.1012 In general, IVIg has been successfully used in many patients and is considered to be safe and well tolerated.7,912 Adverse reactions to IVIg range in severity from mild headaches to rare episodes of stroke.7,13 Individual products vary in their propensity to cause reactions. Also, infusion rates and concentrations of solutions are factors in patient tolerability. Poor venous access in some patients (eg, infants) may result in multiple attempts at venipuncture for each infusion. In some patients indwelling central venous devices are required, with the associated risks of infection and thromboembolic complications. The subcutaneous route of administration of immunoglobulins (SCIg) was initially exclusively used in Sweden.14,15 It has been gradually introduced to the rest of Europe and more recently to North America. Advantages of SCIg include the lack of requirement for vascular access and increased patient autonomy due to self-administration. Disadvantages include frequent injections due to volume limitations of the amount that can be administered at one time and slow buildup of serum Ig trough levels. Lastly, the use of SCIg is contraindicated in patients with bleeding tendencies and in those with various skin conditions. In addition, doses beyond 400600 mg/kg/mo, which are commonly used in autoimmune disorders, cannot be practically administered through the subcutaneous (SC) route. The available Ig products on the market are prepared using the classic Cohn cold alcohol fractionation process, first developed more than 50 years ago.2,3 In this process, plasma from large pools of donors yields a fractionated serum of 95% to 99% IgG and traces of other immunoglobulins.6 The final product must be as free from bacterial and viral contamination as possible. There are several methods for ensuring this, including: donor screening, molecular testing to determine viral load, virus partitioning using Cohn-Oncley fractionation, Kistler-Nitschmann fractionation, chromatography or filtration, virus inactivation using pH 4 incubation, solvent-detergent, heat, caprylate or low pH formulation, and antibody-mediated virus neutralization.16 IVIg and SCIg are available in liquid or lyophilized form. The liquid form takes less preparation before use. Some products require refrigeration, and are available only in one or two concentrations.17 Standard IVIg treatment usually consists of infusions once a month.8,12 The usual maintenance dose for primary immunodeficiency (PID) is 400 mg/kg to 600 mg/kg infused every three to four weeks.8,12 Infusions usually take one to four hours9 and use standard IV administration equipment. Infusions are most commonly administered in a hospital or outpatient setting, but can be administered at home. Pharmacokinetic studies show a rapid increase in serum IgG levels immediately after the infusion (peak) and a subsequent gradual decline (trough). The role of IgG peaks in combating infection remains unknown, but trough levels above 5 g/L appear superior to lower serum IgG levels in preventing infections and improving lung disease.8 In comparison, SCIg therapy consists of weekly or biweekly administration, and the usual maintenance dose is 100 mg/kg, resulting in an accumulated monthly dose similar to that of IVIg therapy.18 The dose is self-administered or parentally administered at home, and the required equipment is tubing, needles or catheters, syringes, and an infusion pump.18,19 The initial infusion rate starts at 10 mL/h, and can be increased until the maximum rate of 22 mL/h is reached.9 Infusions typically take one to four hours.9 SCIg infusions do not result in a peak in serum Ig levels and trough levels rise gradually over a period of up to six months. Consequently, beginning treatment with IVIg and subsequent switching to SCIg is common practice. In preparation for home infusions, patients or parents are typically required to complete four to six educational and

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training sessions at a hospital. Medical and nursing checkups are usually done every fourth week during the training period, including self-infusions under supervision at a clinic. Economic assessment of these modalities of treatment is important and reflects on the health care system evaluated. In this article we have reviewed here studies performed to date including a recent extensive Canadian cost-minimization analysis (CMA).
REVIEW OF ECONOMIC STUDIES

Economic studies were conducted from the perspectives of the health care systems in Sweden, Germany, the UK, and France.2022,24 The characteristics of the four reports are shown in Table 1. The cost parameters and assumptions in each study were reviewed to determine the extent to which the results can be applied to Canadian settings. The results and cost information from these studies appear in Table 2. Several studies have described economic assessments which compare IVIg and SCIg. The studies appear similar in terms of clinical end points, cost items that were included in the analysis, results of the cost-effectiveness analysis, assumption about treatment settings for SCIg and IVIg patients, and assumption about the comparative effectiveness of SCIg and IVIg. The difference between the studies is the degree to which SCIg is cost-effective, owing to differences in study perspectives and differences in the per gram prices of immunoglobulin preparations (which accounts for >78% of the total costs of treatment) across countries. The major assumption in all the studies was equal benefit and harm of IVIg and SCIg. In a cost analysis (CA) study, Gardulf and colleagues21 compared the yearly costs of home- and hospital-based SCIg to those of hospital-based IVIg from the perspective of the Swedish health care system. The per-patient yearly costs associated with IgG preparations, materials, personnel, rooms, and administrative overhead for each Ig therapy were computed. The original values in Swedish kronor were converted to United States dollars (one US$ equals 7.8 kronor), using 1993 prices. The authors used yearly costs to compare hospital-based IVIg with hospital- and home-based SCIg. The yearly cost of hospital-administered SCIg was US$4,656 with more than half (51%) of the cost attributed to IgG preparations. In comparison, the yearly cost of hospital-administered IVIg was US$14,124, and 93% of the cost was attributed to IgG preparations. The yearly cost of SCIg administered at home was US$3,096, with 78% of the cost attributed to IgG preparations. The authors concluded that by replacing hospital-based IVIg with home-based SCIg, the per-patient yearly cost would be reduced by more than US$10,000.21 We identified two issues with the Gardulf and colleagues21 study. First, the implicit assumption in the CA that there was equal effectiveness between the two routes of administration could not be derived from the clinical data presented in the study. Second, the actual cost of therapy by either route of administration may have been underestimated because the study only accounted for costs accrued to the Swedish health care system. The costs associated with transportation of patients, management of adverse events (AE), and time spent by caregivers were not considered in the analysis. Hogy and colleagues20 performed a CMA based on Chapel and colleagues crossover clinical study,23 which found no differences in efficacy or adverse reaction rates between Ig therapy given subcutaneously or intravenously. The CMA took the perspective of the German statutory health insurance, including only those costs that could be reimbursed (eg, costs due to Ig, premedication for IVIg patients,

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Table 1 Characteristics of economic studies Author and Country Gardulf et al,21 Sweden Study Design, Perspective, Interventions CA Swedish health care system Home SCIg versus hospital SCIg and hospital IVIg CMA German statutory health insurance Home SCIg versus hospital IVIg CMA UK health system Application of appropriate UK assumptions to Hogy et al37 cost calculations Home SCIg versus home IVIg and hospital IVIg CA Public payer (France) Home SCIg versus hospital SCIg and hospital IVIg Study Population 165 PID patients aged 13 years to 76 years Clinical Outcomesa Frequency of adverse systemic reactions, occurrence and intensity of tissue reactions and serum IgG changes Used result of previous study, involving 30 PID patients that showed no significant differences in infection and AE rates between SCIg and IVIg As in Hogy et al; no significant differences in infection and AE rates between SCIg and IVIg Cost Considered Ig preparation, materials, personnel, rooms, administrative overhead Ig, pre-medications, infusion pump, physicians, diagnostic procedures, sick leave for childrens caregivers

Hogy et al,20 Germany

Subgroup analysis: adults (75 kg) and children (40 kg)

Liu et al,24 UK

Hogy et al subgroup analysis: adults (75 kg) and children (40 kg)

As in Hogy et al; Ig, pre-medications, infusion pump, infusion materials, physicians, diagnostic procedures, sick leave for childrens caregivers Hospital admission, transportation to and from hospital, Ig acquisition cost (pre-tax), homecare nursing, rental cost of administration pumps and perfusion kits

Haddad et al,22 France

Not stated

No clinical data provided; authors assume equal effectiveness between SCIg and IVIg

Abbreviations: AEs, adverse events; CA, cost analysis. a Primary outcome: infection rate; secondary outcome: AE rate, serum Ig levels.

Table 2 Results of reviewed economic studies Author (Funding Source) Gardulf et al21 (Swedish Medical Research Council) Hogy et al20 (funding source unstated) Sensitivity Analysis on Cost Parameters Not performed Study End Point Total yearly cost of SCIg treatment (home and hospital) versus IVIg treatment (hospital) Total yearly cost of SCIg treatment versus IVIg treatment for each subgroup Study Results Hospital-based IVIg 5 $14,124/y Hospital-based SCIg 5 $4,656/year Home-based SCIg 5 $3,096/year (costs in US$ at 1993 prices) Adult: IVIg 5 V31,027; SCIg 5 V14,893 Children: IVIg 5 V17,329; SCIg 5 V8,659 (costs in 2003 prices) Adult: IVIg at home 5 11,580 Adult: IVIg at hospital 5 18,600 Adult: SCIg at home 5 11,760 Children: IVIg at home 5 6,540 Children : SCIg at home 5 6,720 Hospital IVIg (20 g/mo) 5 V1,192.19 Home IVIg (20 g/mo) 5 V1,033 Home IVIg (40 g/mo) 5 V2,034.50 Hospital SCIg (20 g/mo) 5 V2,908.76 Home SCIg (20 g/mo) 5 V1,518 Home SCIg (40 g/mo) 5 V2,507V2,729

Economic Assessment of Immunoglobulin Replacement Therapy

Patients weight; monthly Ig dose; price/g of IVIg and SCIg; costs of pump, treatment procedures, and pre-medications; and sick leave Not performed

Liu et al24 (funding source unstated)

Total yearly cost of SCIg treatment versus IVIg treatment for each subgroup (costs in 2005 ) Monthly treatment cost of SCIg and IVIg

Haddad et al22 (funding source unstated)

Not performed

865

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Table 3 Base-case costs and assumptions IVIg Item Adults weight Childs weight Monthly Ig dose, adult SCIg NA Home 28 g Hospital Assumptions 70 kg 40 kg Average monthly dose/kg of body weight 0.4 g for either route Liu et al24 Source Hogy et al,20 Liu et al,24 PID Survey27

Monthly Ig dose, child Dosing intervals

Weekly

16 g

Monthly CBS (Mathias Haun, personal communication, 2007) and ZLB (David Barnes, personal communication, 2007) National cost list,26,32,a

Ig price/g Monthly treatment or diagnostic cost

C$57.75 NA

C$57.75 C$87.00 4 h of nurses time plus physicians fees, costs are same for home- and hospital-based IVIg Same charges for adult and child; cost covers infusion materials, administrative support, data management, and follow-ups Similar pump prices for child and adult patients, 2 pumps required/ patient, 1 pump lasts 5 years

Monthly hospital charges

NA

NA

C$110.72

Calculated using expert opinion and National cost list26

Infusion pump cost/y

C$525.12

NA

Berger,18 Hogy et al20 Liu et al24 http://www. marcalmedical.com

Infusion material cost /y for home IVIg and SCIg

C$377.43

C$377.43

NA

Same costs of infusion materials for SCIg and home-based IVIg; for hospital-based IVIg, cost included in-hospital charges Once every 6 mo SCIg, and home-based IVIg patients require monitoring by nurse or physician Patient chooses to travel by public transit or taxi; average traveling distance to clinics or hospitals 15 km in Ontario Opportunity cost of time taken to administer home-IVIg or SCI and hospital IVIg is forgone value of unpaid work and paid work respectively

Berger,18 Liu et al,24 Norfolk Medical30

Monitoring costs every 6 mo

C$55.00

C$55.00

NA

Economic Assessment of Immunoglobulin Replacement Therapy

Transportation costs/mo

NA

NA

C$10.50

Ontario Maternity Expert Panel25

Cost of time lost for treatment/h

C$8.56

C$8.56

C$18.92

Statistics Canada;28 Public Health Agency of Canada;29 PID Survey27

Abbreviations: CBS, Canadian Blood Services; IMIg, intramuscular immunoglobulin; NA, not applicable. Liu et al.24 a Expert opinion.

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infusion pumps and materials used with SCIg, treatment and diagnostic procedures, and sick leave for childrens caregivers). The costs of managing AEs and time lost from work for adults were considered to be identical for SCIg and IVIg and thus were excluded. The yearly costs of SCIg and IVIg therapy were derived from the monthly costs for adults and children, calculated as a function of their respective average monthly Ig dose (ie, determined by average body weight and market price per gram of Ig). The quantity of health care resources (treatment and diagnostic procedures) used was obtained from a survey of 18 German PID-treatment centers. All costs were expressed in 2003 euros (V). The base case results show that the yearly costs to treat an adult patient were V31,027 (IVIg) and V14,893 (SCIg). The yearly costs for a child were V17,329 (IVIg) and V8,659 (SCIg). For both subgroups, Ig acquisition costs were the main cost driver, accounting for >80% of the total yearly cost for each treatment arm. One-way sensitivity analyses were conducted to factor in the uncertainties and variations in resource use, average body weight, monthly dose, and prices. In adult patients, the incremental costs between IVIg and SCIg were more sensitive to changes in the price of Ig and less so to the changes in body weight. In children, the incremental costs were most responsive to changes in body weight. The study by Hogy and colleagues20 showed that compared to IVIg, SCIg was cost saving because its price was 50% cheaper. However, this may not hold in the long-run as market forces will likely eliminate such per-unit cost differences. The study did not itemize the resources included in the calculations. As a result, it was unclear whether overhead costs and hospital charges were accounted for. Moreover, the ability to generalize the results is questionable, because the authors did not describe the methods used for the survey that was the basis for most of the cost calculations. More recent work by Liu and colleagues24 was instrumental in examining the cost drivers associated with IVIg and SCIg. The authors did not develop a new analysis, but investigated whether Hogy and colleagues20 costing assumptions applied in the United Kingdom (UK). This involved an examination of the cost parameters used in Hogy and colleagues20 study and their underlying assumptions, followed by application of the appropriate UK costs parallel to the original German costs. An average 2003 monthly exchange rate of one pound () for V1.453 and an annual inflation rate of 2.9% were used to calculate the equivalent UK costs in for 2005. Regarding the costing assumptions between the two countries, Liu and colleagues24 established that IVIg and SCIg are administered at home and in the hospital in the UK. In adults, the yearly price and cost of treatment or diagnostic procedures for IVIg were lower in the UK than in Germany (ie, 10,800 versus 22,194 and 180 versus 407 respectively). The yearly cost of a SCIg pump was higher in the UK (180 versus 113). The costs associated with sick leave for caregivers of children and senior/disabled adult patients receiving IVIg and SCIg did not apply in the UK, and the costs due to infusion materials and hospital charges for IVIg (originally excluded in Hogy and colleagues study) were applied in the UK costing assumptions. The remaining cost parameters (ie, SCIg price, premedication for IVIg patients, and materials used for SCIg) were applicable and within the reasonable cost range in the UK. The results of Liu and colleagues24 study showed that the yearly costs for homebased IVIg and SCIg therapy were similar: 11,580 (IVIg) and 11,760 (SCIg) per year for adults and 6,540 (IVIg) and 6,720 (SCIg) per year for children. However, the cost of hospital-based IVIg was significantly higher at 18,600 per year. The differences in cost were attributed to hospital services, infusion materials, and treatment and diagnostic procedures for IVIg patients.

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Haddad and colleagues22 compared the monthly costs of treatment between IVIg and SCIg from the perspective of the public payer in France. The comparison involved six treatment alternatives: hospital 20 g IVIg, hospital 20 g SCIg, home 20 g IVIg, home 20 g SCIg, home 40 g IVIg, and home 40 g SCIg. The costs due to hospital admission, transportation to and from hospital, pre-tax Ig acquisition, homecare nursing, and rental of administration pumps and perfusion kits were included. The treatment intervals were set at once per month for IVIg and four times per month for SCIg patients. The base-case monthly costs of treatment were:     IVIg 20 g 5 V1,192.19 (hospital) and V1,033 (home) SCIg 20 g 5 V2,908.76 (hospital) and V1,518 (home) IVIg 40 g 5 V2,034.50 (home) SCIg 40 g 5 V2,507V2,729 (home)

The acquisition and hospital costs for either route of administration were major cost drivers. For example, with IVIg 20 g, approximately 57% of the total treatment cost is due to the cost of Ig, and 39% is due to hospital charges. For SCIg, approximately 30% of the total treatment cost is due to the cost of Ig, and 64% is due to hospital charges. When Ig was administered at home (by IV or SC), the IVIg patient had lower costs associated with the rental of administration pumps and perfusion kits, and IVIg acquisition.
PRIMARY ECONOMIC ASSESSMENT IN CANADA

In the present study, SCIg and IVIg were assumed to yield identical clinical outcomes, as per Chapel and colleagues.23 The base-case results from the CMA for an adult and a child by treatment appear in Tables 4 and 5 respectively. These results show that for each treatment arm, Ig prices account for >85% of the total cost of therapy. The results show a cost difference between SCIg and hospital-based IVIg therapies of about $2,000 Canadian dollars (C$) each year per patient, when indirect costs are included; and a cost advantage for home-based IVIg compared with SCIg. The difference is about C$1,400 per year per patient when indirect costs are excluded.

Table 4 Results of adult yearly cost by treatment in Canada IVIg Cost Items Immunoglobulin Treatment by physician and nurse Hospital Infusion pump Infusion materials Monitoring Total direct treatment Transportation Time lost because of treatment Total direct and indirect Abbreviation: NA, not applicable. SCIg C$19,404.00 NA NA C$525.12 C$377.43 C$110.00 C$20,416.55 NA C$616.32 C$21,032.87 Home Based C$19,404.00 NA NA NA C$377.43 C$110.00 C$19,891.43 NA C$410.88 C$20,302.31 Hospital Based C$19,404.00 C$1,044.00 C$1,328.64 NA NA NA C$21,776.64 C$126.00 C$1,135.20 C$23,037.84

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Table 5 Results of child yearly cost by treatment in Canada IVIg Cost Items Immunoglobulin Treatment by physician and nurse Hospital Infusion pump Infusion materials Monitoring Total direct treatment Transportation Time lost because of treatment Total direct and indirect Abbreviation: NA, not applicable. SCIg C$11,088 NA NA C$525.12 C$377.43 C$110.72 C$12,101.27 NA C$616.32 C$12,717.59 Home Based C$11,088 NA NA NA C$377.43 C$110.72 C$11,576.15 NA C$410.88 C$11,987.03 Hospital Based C$11,088 C$1,044.00 C$1,328.64 NA NA NA C$13,460.64 C$126 C$1,135.20 C$14,721.84

Table 6 Base-case parameters, ranges of sensitivity analysis, and rationale Item Adults weight Childs weight Ig monthly dose/kg body weight IVIg price/g SCIg price/g Infusion pump (SCIg) cost Infusion materials cost Treatment costs (hospital IVIg) Transportation cost (hospital IVIg) Monitoring cost (SCIg and home IVIg) Time lost because of treatment (SCIg) Hospital charges (IVIg) Time lost because of treatment (home IVIg) Time lost because of treatment (hospital IVIg) Base-Case Parameters 70 kg 40 kg 0.4 g C$57.75 C$57.75 C$525.12/y C$377.43/y C$1,044.00/y C$10.50/mo C$55.00/6 mo C$8.56/h (unpaid work) C$1,328.64/y C$8.56/h (unpaid work) C$18.92/h (paid work) SensitivityAnalysis Range 4595 kg 270 kg 0.15 g0.60 g C$50.0070.00 C$50.0070.00 C$262.56787.68 C$188.71566.14 C$522.001,566.00 C$5.0020.00 C$0.00220.00 C$4.2825.68 C$664.32$1992.96 C$8.5651.36 C$18.92151.36 Rationale for Range 25 kg Infant to adult Range reported from PID survey27 Current range (CBS) CBS range 50% 50% 50% Bus fare to taxi fare 04/y 0.53 h/infusion (once a month) 50% 16 h/infusion (once a month) 26 hours/infusion

Abbreviation: CBS, Canadian Blood Services (Mathias Haun, personal communication, 2007).

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Hospital charges Treatment/diagnostic Infusion pump Infusion materials Monitoring Transportation cost Time lost for treatment Per gram IVIg price Per gram SCIg price Adult body weight -3000 -2050 -2000 -1500 -1000 -500 0

Yearly Cost difference (SCIg - Hospital IVIg) - adult

Fig.1. Adults (SCIg and hospital IVIg). IVIg, intravenous immunoglobulin; SCIg, subcutaneous immunoglobulin.

Two factors explain the small cost difference between the two routes. First, the Ig acquisition cost that constitutes most of the total costs for each treatment alternative is similar. Second, for SCIg therapy, the high prices of the pump, monitoring, and infusion materials offset approximately half the gains from averted hospital charges and treatment or diagnostic costs. In the sensitivity analysis, we varied each cost driver to account for uncertainty in the use of resources for each subgroup. We recorded the resulting incremental cost differences for each parameter to determine their respective magnitude of influence to the base-case incremental cost differences. The sensitivity ranges for each parameter, with the justification, are tabulated against base-case parameters in Table 6. The results of the sensitivity analysis are shown in tornado diagrams, depicting the influence of each parameter on incremental cost. Tornado diagrams for children are replicas of those for adults, because the dollar value for each variable (except the per gram price of Ig that is the same for each intervention) is applied to adults and children. Except for the first comparison, we display only the adult tornado diagrams. For adults (Fig. 1) and children (Fig. 2), the results of the sensitivity analysis show that the yearly incremental cost differences between SCIg and hospital-based IVIg are more responsive to hospital charges, treatment costs, costs of infusion pumps, and costs of infusion materials. Overall, the cost differences are not driven by the per gram price of IVIg and SCIg, because they are assumed to be in the same range.

Hospital charges Treatment/diagnostic Infusion pump Infusion materials Monitoring Transportation cost Time lost for treatment Per gram IVIg price Per gram SCIg price Child body weight -3000 -2500 -2000 -1500 -1000 -500 0

Yearly Cost difference (SCIg - Hospital IVIg) - Child

Fig. 2. Children (SCIg and hospital IVIg). IVIg, intravenous immunoglobulin; SCIg, subcutaneous immunoglobulin.

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Hospital charges Time lost for treatment Infusion materials Monitoring Transportation cost Treatment/diagnostic IVIg price Adult body weight

-4000

-3500

-3000

-2500

-2000

-1500

-1000

-500

Yearly cost difference (home IVIg - hospital IVIg)

Time lost for treatment Infusion pump Ig price Monitoring Infusion materials Bodyweight

-1200

-1000

-800

-600

-400

-200

Yearly cost difference (home IVIg -SCIg)

Fig. 3. (A) Yearly incremental cost difference (home IVIghospital IVIg). (B) Yearly cost difference (home IVIgSCIg).

Hospital charges, time lost because of treatment, and infusion materials are major drivers of the cost differences between home-based IVIg and hospital-based IVIg (Fig. 3A). The yearly incremental cost differences between SCIg and home-based IVIg are responsive to the cost of infusion pumps and time lost because of treatment. The per gram prices of SCIg and IVIg, infusion materials, body weight, and monitoring were assumed to be in the same sensitivity range between the two interventions. Therefore, they do not influence the cost differences (Fig. 3B). We have shown here that differences in cost effectiveness between hospital-based IVIg and home based IVIg or SCIg are modest. Home IVIg appeared to be the potentially most cost saving Ig route of administration. Home SCIg, although to a lesser degree, could also save costs when compared with hospital IVIg. Future studies should determine the safety and long term efficacy of home treatment.
SUMMARY

In spite of major differences in the health care systems in various countries, some common themes emerged. First, because the cost of Ig constitutes the lions share of this therapy, lower costs of SCIg in some countries influenced cost analysis studies in favor of SCIg when compared with IVIg. Second, if SCIg and IVIg costs are comparable, then home-based treatment appears more cost effective than hospital-based therapy. The extent of this advantage varies among countries.

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In Canada the CMA show only minimal cost differences between the two treatments. This is attributed to the parity pricing per gram of SCIg and IVIg in this country, and the fact that the acquisition cost of Ig made up the largest proportion of total costs of either treatment. In our analysis, the cost differences resulted from differences between the sums of transportation costs, hospital charges, and treatment or diagnostic charges for hospital-based IVIg and infusion pumps, infusion materials, and monitoring for SCIg. As a result, we found the cost difference between treatments to be small, because the costs due to the materials required for SCIg infusion offset most of the gains from the avoidance of hospital and treatment or diagnostic charges. As a result, home-based IVIg shows a larger net gain from the avoidance of hospital charges.
REFERENCES

1. Cooper MD, Schroeder HW. Primary immune deficiency diseases. In: FD, Kasper DL, Fauci SA, editors. Harrisons principles of internal medicine. 16th edition. New York: McGraw-Hill; 2005. p. 193947. 2. Cohn EJ, Strong LE, Hughes WL, et al. Preparation and properties of serum and plasma proteins. IV: a system for the separation into fractions of protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 1946;68: 45975. 3. Cohn E. The separation of blood into fractions for therapeutic value. Ann Intern Med 1947;26:34152. 4. MacLennan S, Barbara JA. Risks and side effects of therapy with plasma and plasma fractions. Best Pract Res Clin Haematol 2006;19(1):16989. 5. Roifman CM, Lederman HM, Lavi S, et al. Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease. Am J Med 1985;79(2):1714. 6. Rousell RH, Pennington JE. An historical overview of immunoglobulin therapy. In: Yap PL, editor. Clinical applications of intravenous immunoglobulin therapy. New York: Churchhill Livingstone; 1992. p. 115. 7. Nowak-Wegrzyn A, Lederman HM. Supply, use, and abuse of intravenous immunoglobulin. Curr Opin Pediatr 1999;11(6):5339. 8. Roifman CM, Levison H, Gelfand EW. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet 1987;1(8541):10757. 9. Stiehm ER. Appropriate therapeutic use of immunoglobulin. Transfus Med Rev 1996;10(3):20321. 10. Roifman CM, Balter M, Blanchette V, et al. The Consensus Working Group. Present and future uses of intravenous immune globulin (IVIG): a Canadian multidisciplinary consensus-building initiative. Toronto: Maclean Hunter Healthcare/ Sante; 1997. 11. Hanna K, et al. Intravenous immune globulin use in Canada. Can J Clin Pharmacol 2003;10(1):116. 12. Lemieux R, Bazin R, Neron S. Therapeutic intravenous immunoglobulins. Mol Immunol 2005;42(7):83948. 13. Lederman HM, Roifman CM, Lavi S, et al. Corticosteroids for prevention of adverse reactions to intravenous immune serum globulin infusions in hypogammaglobulinemic patients. Am J Med 1986;81(3):4436. 14. Gardulf A, Hammarstrom L, Smith CI. Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet 1991;338(8760): 1626.

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15. Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficienciesa prospective, multinational study. J Clin Immunol 2006;26(2):17785. 16. Schleis T. SJ Formulary considerations for IGIV products. East Rutherford (NJ): U.S. Pharmacist; 2005. 17. Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):40812. 18. Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol 2004;112(1):17. 19. Helbert M, Farragher A. Subcutaneous immunoglobulin for patients with antibody deficiency. Br J Hosp Med (Lond) 2007;68(4):20610. 20. Hogy B, Keinecke HO, Borte M. Pharmacoeconomic evaluation of immunoglobulin treatment in patients with antibody deficiencies from the perspective of the German statutory health insurance. Eur J Health Econ 2005;6(1):249. 21. Gardulf A, Andersen V, Bjorkander J, et al. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 1995;345(8946):3659.   22. Haddad L, Perrinet M, Parent D, et al. Etude comparative du cout du traitement a   domicile des immunoglobulines intraveineuses ou sous-cutanees a visee substitutive. Rev Med Interne 2006;27(12):9246. 23. Chapel HM, Spickett GP, Ericson D, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 2000;20(2):94100. 24. Liu Z, Albon E, Hyde C. The effectiveness and cost effectiveness of immunoglobulin replacement therapy for primary immunodeficiency and chronic lymphocytic leukaemia: a systematic review and economic evaluation. Birmingham (UK): Department of Public Health and Epidemiology, University of Birmingham; 2005. 25. Ontario College of Family Physicians. Babies cant wait - Ontario College of Family Physicians project summary. Available at: http://meds.queensu.ca/prn/ downloads/OMCEP%20App_H_to_I.pdf. Accessed May 30, 2007. 26. Jacobs P, Assiff L, Bachynsky J, et al. A national list of provincial costs for health care: Canada 1997/8. Version 1.0. Edmonton (Canada): Institute of Health Economics; 2000. 27. Treatment experiences and preferences of patients with primary immune deficiency diseases: first national study. Available at: http://www.primaryimmune. org/pubs/IDF_survey_complete.pdf. Accessed August 2, 2007. 28. Statistics Canada. Payroll employment, earnings and hours. The Daily. December 21, 2006. Available at: http://www.statcan.ca/Daily/English/061221/d061221c. htm. Accessed June 7, 2007. 29. Stephens T, Joubert N. The economic burden of mental health problems in Canada. Chronic Dis Can 2001;22(1):1823. 30. Norfolk Medical [price catalog]. Skokie (IL): Norfolk Medical Products, Inc.; 2005.

Ma nagement of Primar y Antibo dy Deficienc y with Replacement Therapy : Summar y of Guidelines

Chaim M. Roifman, MD, FRCPCa,*, Melvin Berger, MD, PhDb, Luigi D. Notarangelo, MDc
KEYWORDS  Primary antibody deficiency  IgG replacement  Intravenous immunoglobulin

In managing primary antibody deficiency with replacement therapy, the following guidelines should be observed: 1. All patients should be referred to an immunologist for diagnosis and initiation of treatment. Long-term management can be shared with family physicians and pediatricians. 2. The following investigations should be performed as appropriate in individual cases: Blood cell count and differential Serum immunoglobulins Antibody titers to immunizations with protein antigens, as well as polysaccharide antigens, (at age greater than 24 months) Polymerase chain reaction assay for HIV and other chronic viral infections (hepatitis B and C) Lymphocyte surface marker analysis Lymphocyte function tests such as mitogen and antigen proliferation Liver and renal function tests Assessment of end-organ damage may be required including Lung function
Division of Immunology and Allergy, Department of Paediatrics, The Research Institute of Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8 b Jeffrey Modell Center for Primary Immune Deficiencies, Division of Allergy-Immunology, Rainbow Babies and Childrens Hospital, University Hospitals of Cleveland, Cleveland, OH, USA c Harvard Medical School, Division of Immunology, Childrens Hospital, Boston, MA, USA * Corresponding author. E-mail address: croifman@sickkids.ca (C.M. Roifman). Immunol Allergy Clin N Am 28 (2008) 875876 doi:10.1016/j.iac.2008.07.003 immunology.theclinics.com 0889-8561/08/$ see front matter 2008 Elsevier Inc. All rights reserved.
a

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3.

4.

5.

6.

7.

8.

9.

10.

CT scans of lung and sinuses Gastrointestinal endoscopy Bone marrow and/or liver biopsy Detailed mutation and additional molecular analyses of the immunologic defect should be considered when appropriate. Patients who have significant antibody deficiency require doses of intravenous immunoglobulin (IVIG) between 0.4 and 0.8 g/kg every 3 to 4 weeks (or the equivalent given in divided doses once or twice a week subcutaneously) to achieve trough IgG serum levels of at least 5 g/L (ideally, 6.510 g/L). If IgG half-life is shorter than 3 weeks and/or if treatment effects are not satisfactory, the frequency of infusions may be increased to every 2 weeks and/or the dose may be increased. In patients who have significant antibody deficiency, IgG replacement should be given regularly and should not be interrupted. IVIG should not be given intermittently because effective serum IgG trough levels may drop to nonprotective levels on cessation of treatment. The first three infusions ideally should be given in a qualified center for monitoring of severe adverse reactions. Subsequent infusions can be administered by family physicians in community hospitals or at home by homecare nurses. After replacement therapy has been established, pretreatment serum IgG trough levels should be obtained monthly and should be followed by an immunology specialist at least every 6 months to monitor treatment effectiveness and complications. Individual patients may require more frequent visits with the immunologist and/or other specialists. If a patient experiences severe adverse reactions to a licensed IVIG product, a different brand of IVIG or subcutaneous IgG should be tried. If adverse reactions persist, premedication with corticosteroids, antihistamines, and/or antipyretics frequently is effective. Slowing the infusion rate should alleviate minor reactions. If it has been established that a patient tolerates only certain brands, the brand of IgG given to that patient should not be changed without obtaining permission from the responsible immunologist. Subcutaneous IgG should be offered as substitute for IVIG for patients who have poor intravenous access. Because subcutaneous immunoglobulin can be self-administered safely at home, it has been offered as an alternative for selected patients. Patients who have developed chronic lung disease (bronchiectasis) should receive special attention. The minimal monitoring regimen is yearly assessment including a pulmonary function test and biannual CT scans. Aggressive antibiotic treatment is needed during acute exacerbations of lung disease. Prolonged or continuous antibiotic treatment may be helpful in chronically infected patients, and these patients often need adjuvant therapies such as physiotherapy, bronchodilators/inhaled corticosteroids, and percussion devices to promote pulmonary toilet. If bronchiectasis is localized and cannot be controlled adequately with IVIG and antibiotics, a lobectomy should be considered. Indications for IgG replacement include common variable immunodeficiency, X-linked agammaglobulinemia, autosomal-recessive agammaglobulinemia, hyperIgM syndromes, dysgammaglobulinemia, or antibody deficiencies associated with syndromes such as Wiskott Aldrich syndrome, ataxia telangiectasia, and others.

It is recommended that analysis and interpretation be performed by immunologists in immunology service laboratories who have the experience, knowledge, and skill to perform DNA sequencing, protein immunoblotting, and, ideally, analysis of the functional pathway of the target gene.