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Immune globulin therapy in primary immunodeficiency

Immune globulin therapy in primary immunodeficiency
Author:
Jordan S Orange, MD, PhD
Section Editor:
Rebecca Marsh, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: Oct 18, 2022.

INTRODUCTION — Polyclonal immune globulin consists of immunoglobulins (mostly immunoglobulin G [IgG]) purified from pooled human plasma. Immune globulin is used to treat a wide variety of diseases, including primary and secondary immunodeficiency states and hematologic and autoimmune disorders [1].

Terminology — Immune globulin, intravenous (human) will be referred to as "IVIG" in this review because this term is commonly used by clinicians, although the abbreviation preferred by various regulatory agencies is "IGIV." Immune globulin can also be administered subcutaneously. Immune globulin, subcutaneous (human) will be referred to as "SCIG."

The use of immune globulin in primary immunodeficiency will be reviewed here. General principles in the use of IVIG and SCIG and the role of these agents in the treatment of various hematologic and autoimmune disorders are presented separately. (See "Overview of intravenous immune globulin (IVIG) therapy".)

Comparisons of intravenous and subcutaneous therapy, both traditional and hyaluronidase-facilitated, are discussed elsewhere. (See "Subcutaneous and intramuscular immune globulin therapy".)

INDICATIONS — Immune globulin therapy is the mainstay of treatment for a variety of primary immunodeficiency states [1-3].

B cell immunodeficiencies — B cell immunodeficiencies for which immune globulin therapy is indicated include the following [1,3-5]:

Bruton (or X-linked) agammaglobulinemia as well as autosomal and other agammaglobulinemias in which there is aberrant B cell development and near absence of B cells in the peripheral circulation. (See "Agammaglobulinemia".)

Common variable immunodeficiency. (See "Treatment and prognosis of common variable immunodeficiency".)

Hyperimmunoglobulin M syndromes, including defects of the CD40 ligand (CD154)-CD40 system, and in other conditions in which there are defects in B cell costimulation and isotype class-switching. (See "Hyperimmunoglobulin M syndromes".)  

Primarily antibody deficiencies, as classified by the IUIS (category I), which include an increasingly defined number of molecular explanations for impaired antibody production [6]. These genetic disorders are caused by aberrations in the germline DNA and are unlikely to improve, making a strong case for indefinite immunoglobulin replacement therapy.

"Milder" B cell deficiencies, such as specific antibody deficiency (an inability to produce antibodies against bacterial polysaccharides), for which immune globulin may be indicated depending upon the severity of the clinical presentation, the history of infections, and responses to vaccine antigens. (See "Specific antibody deficiency".)

Combined immunodeficiencies — Immune globulin is also used in patients with any form of combined immunodeficiency who have not undergone hematopoietic cell transplantation (HCT). In addition, some forms of combined immunodeficiency cause milder impairment of T cell function and do not necessitate HCT but do require lifelong immune globulin replacement. Among patients who have already undergone HCT, immune globulin therapy is frequently required for at least one year after the transplant because full B cell function takes longer to reconstitute than T cell numbers or function. A significant fraction of patients may fail to reconstitute B cell function and may require lifelong immune globulin therapy, even after HCT. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

Other specific primary immunodeficiencies — There are numerous other primary immunodeficiencies in which the production of antibodies is or can be abnormal. In these disorders, B cell function and or numbers can be impaired, leading to an inability to generate effective antibody responses. Whenever aberrant B cell responses are present, immune globulin therapy may be indicated.

The disorders for which immunoglobulin is variably used fall into three categories [6]:

Milder forms of combined immunodeficiencies (such as that caused by partially functional mutations in recombinase-activating genes [RAG] 1 and 2)

Combined immunodeficiencies with associated or syndromic features (such as Wiskott-Aldrich syndrome)

Diseases of immunodysregulation (such as CD27 deficiency)

Immune globulin therapy may also be indicated in states where B cells have been impaired, such as post-transplantation or where specific antibody production is impaired (even when the total immunoglobulin G [IgG] level is normal or elevated), as in multiple myeloma and other gammopathies, B cell lymphoma, and chronic lymphocytic leukemia. It is also important to consider instances where the B cells may have been depleted owing to a therapeutic intervention such as in the use of rituximab or chimeric antigen receptor T cells directed against CD19 as therapy for B cell malignancy. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab'.)

Immune globulin replacement therapy remains controversial in the treatment of physiologic immunodeficiencies identified in very low birthweight premature babies and in a variety of other conditions for which anecdotal therapeutic successes have been reported [1]. (See "Transient hypogammaglobulinemia of infancy".)

EFFICACY

Prevention of bacterial infections — The primary goal of immune globulin therapy in patients with primary immunodeficiencies is the prevention of sepsis, pneumonia, and other serious acute bacterial infections. These are the major criteria for licensing purposes [7]. All adequately designed studies of intravenous immune globulin (IVIG) for the treatment of immunodeficiency have demonstrated these clinical benefits for immune globulin products licensed in the United States by the US Food and Drug Administration (FDA) for replacement therapy in primary immunodeficiency.

Most of these studies report rates of infections in a specific population of patients before and after immune globulin was initiated, since the importance of this therapy in immunodeficient patients prohibits the performance of placebo-controlled studies. As an example, a review of IVIG therapy for common variable immunodeficiency found that 84 percent of a cohort of 50 patients experienced at least one episode of bacterial pneumonia prior to therapy [8]. During IVIG treatment (mean period of observation 6.6 years, range 1 to 26 years), only 11 percent of patients experienced bacterial pneumonia.

Estimates of the size of the treatment effect are dependent upon several variables, including the serum immunoglobulin G (IgG) levels achieved, the patient's underlying primary immune disorder, and associated conditions, such as bronchiectasis. However, several studies have confirmed the aggregate clinical impression that higher serum IgG levels are associated with increased freedom from infection [9-12]. (See 'Individualizing the dose' below.)

In addition to serious acute infections, patients with immunodeficiency may also have subclinical chronic infection of the lungs and/or sinuses, which can result in bronchiectasis and progressive loss of pulmonary function. It is presumed that immune globulin therapy, if given in sufficient doses, can ameliorate the long-term consequences of these conditions, although adequate longitudinal studies have not been performed. In patients with primary immunodeficiency who have existing chronic lung disease, higher doses of immunoglobulin have been associated with quantifiable benefits [13]. (See "Treatment and prognosis of common variable immunodeficiency", section on 'Indications for higher dosing'.)

The impact of immune globulin on infections in various conditions is discussed in specific topic reviews. (See "Treatment and prognosis of common variable immunodeficiency", section on 'Immune globulin replacement therapy' and "Agammaglobulinemia", section on 'Management'.)

Other benefits — Studies of immune globulin therapy also document other benefits to patients, which are achieved as secondary goals, including a decreased incidence of viral and bacterial upper respiratory tract infection and bronchitis, reduced antibiotic use, fewer hospital admissions, improved pulmonary function, and improved growth and quality of life [14]. Among patients with primary immunodeficiencies, regular treatment with immune globulin is associated with higher scores of perceived health [15].

Limitations of therapy — Immune globulin replacement therapy does not correct all of the manifestations of primary immunodeficiency diseases. As an example, patients with common variable immunodeficiency may be protected from clinical pneumonia by immune globulin treatment [8], but they can continue to experience chronic or recurrent sinusitis, progression of lung disease, or certain ongoing autoimmune disorders. (See "Treatment and prognosis of common variable immunodeficiency".)

Patients with common variable immunodeficiency are also susceptible to the development of new autoimmune disease and malignancy. There is insufficient evidence to determine if the doses of immune globulin that are adequate to prevent acute infections will also reduce the risk of these complications or even treat autoimmunity, which might otherwise be modified by immune globulin at higher doses.

CONSTITUENTS AND PRODUCTION METHODS — Immune globulin is purified from pooled human plasma, obtained from thousands of donors. The use of many donors helps to ensure that the preparation contains a broad spectrum of protective antibodies and is relatively uniform. However, it also increases the risk of transmission of bloodborne pathogens and has necessitated the use of multiple purification steps. These steps are reviewed in detail separately. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Production and composition' and "Intravenous immune globulin: Adverse effects", section on 'Infectious risks'.)

Immunoglobulins — Intravenous immune globulin (IVIG) and subcutaneous immune globulin (SCIG) principally contain immunoglobulin G (IgG). Most products approximate the distribution of IgG subclasses found in normal plasma, while specific efforts are made to reduce immunoglobulin A (IgA) and immunoglobulin M (IgM).

All production processes begin with cold ethanol fractionation, which is done according to Cohn-Oncley or Kistler-Nitschmann procedures [16,17]. Different manufacturers then use various combinations of precipitation, filtration, and/or chromatography steps to obtain final preparations that consist of greater than 95 percent IgG in all available products. IVIG also contains a small amount of IgA, which varies among the different products (table 1).

Antibodies to specific antigens — Testing of immune globulin to determine the content of specific antibodies is routinely performed only for antibodies to measles, poliovirus, and diphtheria toxin antigen as mandated by the US Food and Drug Administration (FDA) (Code of Federal Regulations [CFR] 640.104) [18]. Aside from these titers, products are neither standardized nor routinely tested for their content of specific antibodies against other pathogens. Thus, product-to-product and lot-to-lot variation in specific antibody titers is likely, although the different preparations are assumed to have equivalent therapeutic efficacy overall in protecting antibody-deficient patients against infection.

Other constituents — Manufacturers use various stabilizers to obtain a final product, and these preparations differ in storage requirements and shelf-life. Stabilizers include sugars, such as glucose, or maltose. Other products contain amino acids, such as glycine or proline. The sodium content of different products varies. The pH and osmolality of products vary as well, but this is not known to be of clinical significance. The resulting products differ from each other in ways that may be important in a particular patient (table 1). There are also numerous differences between available preparations that are of unknown significance [19]. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Selecting a product'.)

INFORMED CONSENT/PATIENT INFORMATION — Several medical centers require signed specific informed consent prior to administering immune globulin and/or other blood products, although this practice is not universal. Regardless of the policy, a discussion with the patient/guardian is indicated prior to administration to discuss the reasons immune globulin therapy is necessary, the fact that treatment is often lifelong, and to review the risks of therapy.

Risks of therapy — Consent should also discuss possible adverse effects, which include headache, infusion reactions, renal complications, hemolytic anemia, neutropenia, thromboembolic events, rare but serious allergic reactions, and the small but theoretic risk of transmission of bloodborne diseases [20]. Adverse effects are reviewed in more detail separately. (See "Intravenous immune globulin: Adverse effects".)

ADMINISTRATION AND DOSING — In the United States, intravenous immune globulin (IVIG) is usually administered in an infusion center or health care facility. It may also be infused in the home setting, usually by a trained home infusion provider. Home infusion may be more cost effective and has been shown to result in improved quality of life measures [21]. Subcutaneous immune globulin (SCIG) is most often self-administered in the home setting by the patient or given to a child by a parent, once training in the appropriate techniques has been accomplished. A third option is facilitated SCIG (fSCIG), in which SCIG is administered along with hyaluronidase that allows for the absorption of a larger dose of SCIG into a single subcutaneous infusion site [22]. With any of these three routes of administration, the first few infusions should be administered with medical supervision. Similarly, it is advisable to ensure that medical supervision is in place if the preparation or brand of immune globulin is changed, as adverse reactions are more likely in this circumstance [1]. (See "Subcutaneous and intramuscular immune globulin therapy".)

Selecting a specific product — There are some circumstances in which one immunoglobulin product may be more suitable than another for a given patient. This is discussed elsewhere, although direct comparative evidence does not exist [23]. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Selecting a product'.)

Pretreatment testing — Before starting immune globulin replacement, the following testing is recommended:

Evaluation for exposure to infection with known bloodborne pathogens, including human immunodeficiency virus (HIV) and hepatitis B and C, to establish the patient's baseline status in case there is ever a question of disease transmission as a result of therapy. Nucleic-acid based tests (polymerase chain reaction [PCR] or reverse transcriptase [RT]-PCR) are preferable to antibody titers in patients with impaired antibody production. Some immunologists also include tests for exposure to parvovirus B19 [24] and transaminases to screen for early hepatitis. The risks of parvovirus and hepatitis infection are discussed separately. (See "Intravenous immune globulin: Adverse effects", section on 'Infectious risks'.)

Complete blood counts because red blood cell hemolysis and neutropenia are rare complications of immune globulin therapy. Direct Coombs testing is not routinely indicated, although it should be done if the patient is anemic or has an illness associated with autoimmunity and hemolytic anemia (eg, common variable immunodeficiency, X-linked hyperimmunoglobulin M syndrome). (See "Intravenous immune globulin: Adverse effects", section on 'Complications affecting the kidney' and "Intravenous immune globulin: Adverse effects", section on 'Hematologic complications'.)

Blood urea nitrogen and/or creatinine because renal problems are a possible complication of immune globulin therapy. Immune globulin should be used with caution in older adults and in patients with renal disease, diabetes mellitus, volume depletion, sepsis, paraproteinemia, and nephrotoxic medications due to risk of renal dysfunction. (See "Intravenous immune globulin: Adverse effects", section on 'Complications affecting the kidney'.)

Some centers test patients with undetectable levels of IgA for the presence of IgG anti-IgA antibodies prior to administering IVIG, although this practice is not specifically recommended by professional immunology societies [3]. In addition, there is evidence for patients with anti-IgA antibodies successfully receiving trace IgA containing IVIG products. The incidence of IgE-anti-IgA antibodies is extremely rare, but true anaphylaxis owing to this mechanism has been documented. (See "Intravenous immune globulin: Adverse effects", section on 'Anaphylaxis and anaphylaxis-like reactions'.)

Administration — Initial doses of immune globulin should always be given under medical supervision, as patients may have a greater risk of adverse reaction with the initial infusion. Issues surrounding the administration of immune globulin include choice of the route (intravenous, subcutaneous, or facilitated subcutaneous), selection of a product, consent, premedication, preinfusion hydration, and infusion rates. These are reviewed separately. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Selecting a product' and "Overview of intravenous immune globulin (IVIG) therapy", section on 'Premedications' and "Overview of intravenous immune globulin (IVIG) therapy", section on 'Consent and record keeping'.)

Initial doses and schedules — A standard initial dose of IVIG for the treatment of antibody-deficient patients is 400 mg/kg (with a range of 400 to 600 mg/kg) every three to four weeks. Standard starting doses for SCIG are in the range of 100 to 200 mg/kg per week [1]. For patients starting on fSCIG, the IVIG monthly dosing considerations apply.

The dose for each patient can be rounded up or down to the nearest full unit in which the immune globulin product is supplied, in order to avoid discarding unused portions of this very costly therapy. The liquid preparations come in several bottle sizes, as do the powders (to a lesser degree). Few pharmacies are able to stock all available sizes and the full range of marketed products due to costs, shortages, and variability in supply. Therefore, it is prudent to consult with the pharmacist preparing the immune globulin and determine how much rounding is necessary to avoid waste.

As an example, if a patient weighing 52 kg is prescribed 400 mg/kg of a 10 percent liquid preparation of IVIG, then the amount of drug required would be (0.4 grams/kg) x (52 kg) x (100 mL/10 grams) = 208 mL. Since the smallest vial of most products contains 10 mL, the dose can be rounded up to 210 mL to avoid wasting the 2 mL. If the pharmacy does not have the 10 mL bottle, then the dose could be rounded down to 200 mL. If necessary, the dosing interval could be adjusted one day or two in either direction to help assure adequacy of therapy.

A loading regimen can achieve steady-state more rapidly and is appropriate in patients with agammaglobulinemia or severe hypogammaglobulinemia (immunoglobulin G [IgG] <200 mg/dL). Intravenous loading can be achieved with a single dose of up to 1 gram/kg. Alternatively, 100 to 200 mg/kg, given on four to five consecutive days could be used as a loading dose, and this approach may have fewer or milder systemic adverse effects. The latter approach is often better tolerated by patients with active infection or those with frail physiology (eg, a neonate, a patient on fluid restriction, those with renal or cardiac disease). Subcutaneous loading can be accomplished by administering 100 to 200 mg/kg daily for five days, although this manner of use is not specifically approved by the US Food and Drug Administration. Most prescribers do not administer loading doses to patients with higher IgG levels (>300 to 400 mg/dL prior to the start of therapy).

In patients initiating therapy during an active infection, it may be prudent to administer only part of the dose initially and to give additional increments over the next several days until the full dose has been administered. This may help to avoid phlogistic reactions associated with active infection. The rate of administration should be slow as well. An example would be starting an infusion at 0.5 mL/kg/hour and increasing by 0.5 mL/kg/hour every 15 minutes until a final infusion rate is achieved. (See "Intravenous immune globulin: Adverse effects", section on 'Pain or systemic (influenza-like) symptoms'.)

The 21- or 28-day dosing interval for intravenous infusions is based upon the half-life of IgG in the circulation, which is normally 21 to 22 days, although great variability among individuals and different immune globulin products exists. Therapeutic levels are reached within one hour of infusion of IVIG, and consistent trough levels are usually achieved after three to six months of therapy. With each intravenous infusion cycle, the peak serum level is typically two to three times the trough level.

Intravenous dosing intervals greater than four weeks are not recommended. Many patients receiving IVIG at intervals of four weeks or longer report increased arthralgias and other musculoskeletal symptoms, "breakthrough" infections, low-grade fevers, and/or feelings of malaise or lethargy toward the end of each treatment interval. In a 2003 survey by the Immune Deficiency Foundation (which was subsequently repeated in a separate survey), 68 percent of patients reported that they could "feel their IVIG wearing off" before their next infusion was due. Many clinicians consider this an indication to shorten that interval to every three or even every two weeks in a stepwise fashion. Intravenous dosing intervals shorter than two weeks are not usually necessary. SCIG should be considered if shorter dosing intervals are desired. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'Comparison of SCIG with IVIG'.)

Trough levels — For patients with hypogammaglobulinemia before therapy, dosing of both IVIG and SCIG should be adjusted primarily based upon the patient's clinical condition. (See 'Individualizing the dose' below.)

If needed, trough levels of IgG should be measured just before an infusion for patients on IVIG. Consistent trough levels are usually achieved after three to six months of regular therapy. There is no specific frequency of trough level measurement that is considered standard of care. Periodic measurement of trough levels will ensure that complications of the primary disease causing protein loss have not occurred to a degree where they affect IgG retention. For those receiving treatment at home, monitoring assures adequate adherence to prescribed regimens. In addition, the dose can be adjusted regularly in growing children in order to maintain a consistent trough level in the face of increasing body mass.

There is no single target trough level that correlates to protection from infection in all patients. One set of guidelines in the United States recommends 500 mg/dL as a minimally acceptable trough level [3], while another suggests that higher trough levels at 800 mg/dL is associated with better outcomes. There are correlations between trough levels and infection for both IVIG and SCIG when patients are considered in aggregate [1,11,12]. Other authorities suggest using an increment of at least 400 mg/dL above the initial pretreatment level as an indicator of adequate replacement. We suggest individualizing the dose for each patient. (See 'Individualizing the dose' below.)

Individualizing the dose — Most patients do well with maintenance intravenous doses of 300 to 600 mg/kg at three-week intervals or 400 to 800 mg/kg at four-week intervals. However, some patients require alternative dosing regimens with either higher or lower doses or dosing intervals shorter than every four weeks in order to accomplish the intended objectives. Thus, there is a wide array of practices applied to patients to achieve best outcomes [25,26].

The dose of immune globulin required to achieve and maintain a desired IgG level depends upon several factors:

The patient's initial serum IgG concentration

The frequency of administration

The IgG half-life of that particular patient

The extent of exposure to infectious disease

Other forms of significant physiologic stress

Some patients metabolize IVIG more rapidly than others and/or may have renal or gastrointestinal losses. The relationship between dose and IgG level may also differ in patients with bronchiectasis compared with those without this complication.

Determining a patient's threshold dose — The target dose of IVIG for a given patient is the dose that protects that individual from significant infections [9,27]. Most patients do well with maintenance doses of 300 to 600 mg/kg at three-week intervals or 400 to 800 mg/kg at four-week intervals or at trough (for those on IVIG) serum IgG levels of approximately 500 to 800 mg/dL. However, some patients appear to derive clinical benefit from IVIG only at trough levels considerably above 800 mg/dL (occasionally above 1000 mg/dL). The data supporting this were evaluated in aggregate in a meta-analysis [11]. The use of higher doses of immune globulin in patients with common variable immunodeficiency is discussed elsewhere. (See "Treatment and prognosis of common variable immunodeficiency", section on 'Indications for higher dosing'.)

Graphing the patient's dose, trough IgG levels (or random levels if the patient is receiving subcutaneous therapy), and infections over time has been suggested as one method of determining the optimal dose for a given individual [27]. A form is provided for doing this, with an example of how it might be completed by a patient (form 1A-B). Some patients demonstrate a threshold level, above which the incidence of infections dramatically decreases. In some patients with chronic infections, the optimal dose of IgG replacement can also be assessed by following the white blood cell count and/or laboratory indicators of infection and/or inflammation, such as the erythrocyte sedimentation rate and/or the C-reactive protein.

If a patient is continuing to get infections, it is prudent to determine if the patient is still adherent to other therapies before increasing the dose or shortening the infusion interval of the immune globulin. For example, patients with asthma or chronic rhinosinusitis who are continuing to get pulmonary or sinus infections should be asked if they are still taking their inhaled or topical nasal glucocorticoid. Sometimes patients will begin to feel better after starting immune globulin and may not be as consistent with concomitant therapies or assume those therapies are no longer needed. It is also important to revisit other conditions that could contribute to symptoms, such as environmental allergies and gastroesophageal reflux.

"Wear-off" effects — Some patients experience symptoms toward the end of the dosing intervals with IVIG, such as increased fatigue, myalgia, and arthralgia or arthritis (sometimes called "wear-off" effects) [28,29]. This has been hypothesized to represent a feature of subphysiologic IgG levels or subphysiologic levels of specific IgG that may result in increased susceptibility to subclinical or clinical infections. In some but not all cases, this can be ameliorated by the addition of adjunct prophylactic antibiotics [30]. Patients who are bothered by these symptoms may benefit from increasing the dose slightly or shortening the infusion interval (changing both dose and interval simultaneously is discouraged) [31]. Alternatively, the patient could be changed to subcutaneous administration, as wear-off effects are rarely seen with SCIG. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'Advantages of SCIG'.)

Patients with normal pretreatment IgG levels — In patients with deficiencies of specific types of antibodies, such as those against polysaccharide antigens or those with "isolated" deficiencies in the antibody repertoire, the antibodies they lack can only be replaced with standard polyclonal immune globulin, and therefore, the trough IgG level may not be a useful indicator of the adequacy of therapy. In those types of partial IgG deficiency, full replacement doses (400 to 600 mg/kg every three weeks or 400 to 800 mg/kg every four weeks) may be necessary, even if the pretreatment serum IgG level is not in the range considered as hypogammaglobulinemic. The total IgG level may be similarly unhelpful in cases in which antibody deficiency coexists with monoclonal gammopathy or polyclonal B cell activation, such as may occur in systemic lupus erythematosus and Epstein-Barr virus-induced lymphoproliferative disease. Thus, patients should be monitored to determine the dose which successfully reduces the incidence and severity of infections for that individual [9,27]. Some immunologists measure specific antibody titers to pathogens for which the patient is at risk (ie, pneumococcal polysaccharides) and use this information to adjust the dose of immune globulin.

Monitoring and record keeping — The dose, brand, lot number, and expiration date of the immune globulin product infused into any patient should be recorded in the medical record, as is done for blood products. This is discussed elsewhere. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Consent and record keeping'.)

Tracking the patient's dose and recording the occurrence of infections is discussed above. (See 'Determining a patient's threshold dose' above.)

Duration of therapy — Immune globulin replacement therapy is usually lifelong for disorders in which antibody levels are extremely low or immune function is globally impaired, especially when there is a genetic mutation identified that defines the disease as a known inherent primary immunodeficiency. In phenotypically (nongenetically) diagnosed common variable immunodeficiency, a single attempt (per lifetime) to stop immune globulin therapy is warranted [1,3], as a small percentage of patients have demonstrated restored humoral immunity after having been treated. For patients with severe immunodeficiencies, hematopoietic cell transplantation (HCT) offers the possibility for donor B cell/T cell reconstitution and restoration of antibody function, although this only effectively occurs in a subset of transplanted patients. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

In milder disorders, such as specific antibody deficiency, there may be scenarios in which therapy is stopped and antibody function is reassessed after a period of time. This is discussed elsewhere. (See "Specific antibody deficiency", section on 'Duration of therapy'.)

Use in pregnancy — Both IVIG and SCIG therapy have been successfully used throughout pregnancy, and the limited information available suggests that the therapy is safe for the developing fetus [32,33]. The dose during pregnancy should be increased as the mother gains weight to ensure that serum IgG levels are adequate and that there is sufficient IgG for transfer across the placenta [33,34]. We suggest increasing the immune globulin dose by 20 to 30 percent in the third trimester. A report of two women with common variable immunodeficiency demonstrated that exogenously administered IgG crossed the placenta normally and was also present in normal or elevated levels in the women's colostrum [35].

The maintenance of normal serum immunoglobulin levels in pregnant women with primary immunodeficiencies may have important benefits for both mother and fetus. Early exposure to maternal IgG is believed to influence the developing immune system of the fetus, and the impact of maternal immunoglobulin deficiency on the fetus in the absence of replacement therapy has not been thoroughly studied. In addition, the presence of normal immunoglobulin levels protects the mother through pregnancy and the peripartum period and provides protective antibody for the newborn. Protection of the newborn is important because adequate IgG production in the baby is not usually achieved until six months of age. Since most of the IgG present in the newborn is transferred transplacentally during the third trimester, preterm babies may have very low IgG levels, putting them at increased risk of infection. (See "Placental development and physiology", section on 'Immunoglobulin G transfer'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Intravenous immune globulin (IVIG or IGIV) and subcutaneous immune globulin (SCIG) are used in a variety of primary immunodeficiency disorders, including primary antibody deficiencies, combined immunodeficiencies prior to transplantation and until B cell function is restored, and other specific disorders involving defects in antibody production or function. (See 'Indications' above.)

When administered to patients with primary immunodeficiencies, immune globulin is effective in reducing the incidence of sepsis, pneumonia, and other serious bacterial infections. Other beneficial effects include reduced antibiotic use, reduced incidence of mild infections, fewer hospital admissions, fewer school/work absences, improved growth (in children), and improved quality of life. (See 'Efficacy' above.)

Different preparations of IVIG and SCIG are available (table 1). Most patients tolerate most products, but there are certain situations in which a specific IVIG product may be desirable. Patients should not be switched from one product to another without permission from the patient's clinician. (See 'Other constituents' above and "Overview of intravenous immune globulin (IVIG) therapy", section on 'Selecting a product'.)

A dose of 400 to 600 mg/kg every three to four weeks is the usual initial dose of IVIG in antibody-deficient patients. Standard starting doses for SCIG are in the range of 100 to 200 mg/kg per week. (See 'Administration and dosing' above.)

The target dose of immune globulin is that dose which keeps that individual patient protected from significant infections. (See 'Individualizing the dose' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Melvin Berger, MD, PhD, who contributed as an author to an earlier version of this topic review.

The UpToDate editorial staff also acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

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