Intravenous immune globulin: Adverse effects

INTRODUCTION — Intravenous immune globulin (IVIG) is a product prepared from human plasma used to treat a variety of immunodeficiency, inflammatory, and autoimmune conditions.

This topic review discusses potential adverse reactions to IVIG, along with strategies to minimize these reactions and our approach to treatment.

Separate topic reviews discuss the clinical uses of IVIG and products for subcutaneous (SC) and intramuscular (IM) administration:

●IVIG products – (See "Overview of intravenous immune globulin (IVIG) therapy".)

●SC and IM products – (See "Subcutaneous and intramuscular immune globulin therapy".)

●Use of immunoglobulin products to treat immunodeficiencies – (See "Immune globulin therapy in inborn errors of immunity".)

OVERVIEW

Terminology — Human immune globulin (also called immunoglobulin, immune serum globulin [ISG], or gamma globulin) is an antibody-containing product purified from large pools (>10,000 liters) of human plasma using techniques that separate the immunoglobulin fraction from other proteins and plasma constituents. (See "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Purification methods'.)

Hyperimmune globulins refer to products made from plasma with a high titer of the desired antibody. Some hyperimmune products are derived from immunized animals (eg, equine products) such as diphtheria antitoxin or snake anti-venoms. These products are much more likely to have adverse reactions, which are outside the scope of this topic review.

Products for intravenous use are referred to as intravenous immune globulin (IVIG) by clinicians and as "IGIV" by industry and regulatory agencies.

Other human immune globulin preparations include subcutaneous immune globulin (SCIG; IGSC, SC ISG), hyaluronidase-facilitated SCIG (fSCIG), and intramuscular immune globulin (IMIG; IGIM, IM ISG). IMIG is rarely used because it has few if any advantages over subcutaneous or intravenous products.

Incidence and risk factors — Adverse reactions are reported to occur in 5 to 15 percent of all IVIG infusions and affect 20 to 50 percent of individuals receiving IVIG [1-7].

More than half of reactions occur in the immediate period during or within a few hours of the infusion, especially with the first infusion or after changing products [8]. (See 'Anaphylaxis and anaphylaxis-like reactions' below and 'Other immediate reactions' below.)

In children, the incidence of adverse effects was evaluated in a prospective series of 345 IVIG infusions administered to 58 children (33 for immunodeficiency and 25 for immunomodulation; median age, four years) [9].

●Adverse events occurred in 40 percent of patients.

●Immediate adverse reactions were seen in 3.5 percent of the infusions and delayed reactions in 20.9 percent.

●Headache was the most common reaction (24 percent of patients, 13 percent of infusions) and most often occurred as a delayed reaction.

Other common reactions include fatigue, abdominal pain, and myalgia [10,11].

The risk of adverse reactions generally correlates with the dose of IVIG within each course and the rate of infusion. Many of the known adverse reactions are more likely to occur during the first infusion, or the first infusion of a new product after changing brands. This was illustrated in a review of 15,548 infusions administered to 1705 patients, in which only 10 individuals had an adverse systemic reaction to a product they had previously received [12]. Adverse reactions are uncommon in patients receiving IVIG on a regular schedule [1,2,13].

Most adverse reactions are mild, transient, reversible events such as headache, chills, or flushing. Potentially serious reactions occur in 2 to 6 percent of patients [14]. Product information includes a Boxed Warning regarding the risks of thrombosis, kidney dysfunction, and acute kidney injury [14].

The underlying clinical condition may also affect the risk spectrum of adverse events. As examples:

●In a review of 13,508 IVIG infusions in 459 patients with primary antibody deficiencies, the presence of a concomitant infection increased the risk compared (5.1 percent, versus 0.5 percent in individuals without an infection) [13].

●In a series of 54 patients with neuromuscular disorders treated with IVIG, the risk of severe headaches and aseptic meningitis was greater in individuals with a history of migraine than in those without a migraine history (4 of 8 [50 percent] versus 2 of 46 [4 percent]) [15].

Additional general risk factors include hyperviscosity states (either from dehydration or a hyperviscosity syndrome due to cryoglobulins or paraproteins), underlying organ dysfunction (eg, kidney disease), and/or prothrombotic stimuli (eg, systemic inflammatory state or central venous catheter). Other risk factors in adults include coronary artery disease, hypertension, smoking, hyperlipidemia, diabetes mellitus, age >65 years, sepsis, immobility, and concomitant use of estrogens or nephrotoxic agents [2,4,16,17]. Adverse events also can occur in individuals who lack predisposing factors.

Changing from a well-tolerated product to another product should be avoided when possible, and changes should not be made without the consent of the patient's clinician [14]. Patients initiating IVIG therapy, or those switching between products, should be observed closely by a clinician who is familiar with the signs and symptoms of IVIG reactions [14]. (See 'Change of products' below.)

Classification of reaction types — Reactions to IVIG can be classified in several ways (by severity, affected organ system, timing of onset, or mechanism).

●Severity – The majority of adverse reactions to IVIG are mild and transient. Potentially severe reactions include anaphylaxis in some immunoglobulin A (IgA)-deficient individuals and thromboembolic events including myocardial and cerebral ischemia, impaired kidney function, aseptic meningitis, or severe hemolysis.

●Organ system – Organ systems that may be affected include the kidney, lungs, skin, central nervous system, gastrointestinal system, and hematopoietic system, including red blood cells (RBCs), particularly hemolytic reactions. Systemic reactions such as anaphylaxis and vascular/thromboembolic complications can affect multiple organ systems.

●Timing – Immediate reactions occur during or within six hours following the infusion and include IgE-mediated anaphylaxis and rate-related reactions such as headache, fever/chills (especially in patients with active infections), and infrequently thromboembolic events. Delayed reactions occur hours to days following the infusion and include headache/aseptic meningitis, acute kidney injury, hemolysis, and thromboembolic events such as venous thrombosis, myocardial infarction, transient ischemic attack, and stroke.

●Mechanism – Potential mechanisms of adverse reactions to IVIG include immune reactions such as complement activation. These may be caused by components in the product (coagulation factors or vasoactive enzymes such as kallikreins) or a reaction to them. Other mechanisms are related to an antibody specificity (hemolytic anemia from isoagglutinins [antibodies to RBC antigens such as A, B, or RhD], although newer products undergo added steps to reduce hemolysis), reactions related to active non-IgG proteins in the product (one product since removed from the market contained an activated clotting factor (see 'Thromboembolic events' below)), and reactions related to excipients such as sucrose (subsequently removed from all products) or the osmotic and/or free water load of the infusion [2].

An approach to distinguishing among some of the immediate reactions is presented in the algorithm (algorithm 1), with the caveat that many IVIG infusions occur in the home or an outpatient setting without access to full radiology and laboratory services.

Comparison with subcutaneous products — SCIG has a lower rate of adverse effects than IVIG and is appropriate for some conditions such as patients with immunodeficiency, as these patients generally require lower doses of immune globulin. One SCIG preparation is approved for use at the larger doses needed for chronic inflammatory demyelinating polyneuropathy (CIDP) and provides another treatment option for these patients [18]. Adverse effects of SCIG are mostly local reactions at the injection site(s). Some side effects from SCIG can be mitigated by more frequent infusion of smaller volumes (eg, dosing multiple times per week instead of weekly or every two weeks).

Other differences between SCIG and IVIG are described separately. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'Comparison of SCIG with IVIG'.)

STRATEGIES FOR REDUCING ADVERSE EVENTS — A variety of strategies are used clinically for minimizing the risk of adverse reactions to IVIG [19]. These are summarized in the table (table 1) and discussed below. It is helpful to reassure patients that minor adverse effects are common and generally improve over time.

Precautions in all patients

●Therapeutic immunoglobulins should only be given for appropriate indications, as discussed in individual disease-specific topic reviews. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Clinical uses'.)

●Administration by the subcutaneous route may reduce the risk of some reactions. Conditions in which this may be appropriate (typically immunodeficiencies) are discussed separately. (See "Subcutaneous and intramuscular immune globulin therapy".)

●Patients should be adequately hydrated prior to starting the infusions. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Prehydration'.)

●Slow infusion rates, with gradual stepwise increases, are suggested for new patients or when products are changed. Stepwise increases in rates following an initially slow infusion are also appropriate for individuals receiving regular IVIG infusions. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Infusion rates'.)

●Once a product has been established to be safe and effective for a given patient, substitutions of other products should be avoided. Changes should be made only if there is a clear clinical rationale and the prescribing clinician and patient agree. (See 'Change of products' below.)

●Patients or designated providers should keep a record of all lots of IVIG and any other blood products received, in case a "look back" is ordered. Most vials of IVIG have a perforated sticker that can be removed and kept in the patient's personal log book, or the lot number can be requested from the hospital pharmacy or other provider. Practices differ; in many cases the transfusion medicine service or infusion center is responsible for documenting lot numbers. For patients receiving IVIG at home, the specialty pharmacy usually tracks the lot numbers dispensed. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Consent and record keeping'.)

Precautions in specific populations

●Patients with a suspected bacterial infection should receive antibiotic therapy before the IVIG infusion to reduce the risk of an excessive inflammatory reaction. (See 'Pain or systemic (influenza-like) symptoms' below.)

●Patients who develop anaphylaxis and who have very low or undetectable IgA levels (<5 to 7 mg/dL) and IgE anti-IgA antibodies require special attention and should switch to subcutaneous immune globulin (SCIG) or receive a product with low IgA; premedications may also be appropriate. This situation is very rare; many individuals with low or absent IgA are able to tolerate IVIG regardless of the IgA content. (See 'Anaphylaxis and anaphylaxis-like reactions' below.)

●Patients who are prone to headaches or have a history of migraine are at increased risk for headaches with infusion and can take a nonsteroidal antiinflammatory drug (NSAID) or acetaminophen prior to, or at the time of, IVIG infusion. Specific regimens and additional measures for more refractory headaches or delayed-onset aseptic meningitis are discussed below. In addition, it can be helpful to remind patients to ensure they are well hydrated the day before and for a day or two after infusion. (See 'Headache and migraine (acute or delayed)' below.)

●Patients at increased risk of thromboembolic complications, or those who have had prior thromboembolic complications, may benefit from additional preventive measures including preinfusion hydration and avoidance of prolonged immobility (eg, airplane travel) in the few days following the infusion, although there is no high-quality evidence to support most of these interventions specifically in individuals receiving IVIG. (See 'Thromboembolic events' below.)

●Patients at increased risk of acute kidney injury or those with underlying chronic kidney disease may be given intravenous fluids before beginning the IVIG infusion to avoid hyperviscosity. (See 'Complications affecting the kidney' below.)

Additional measures may include:

•If the patient cannot tolerate a more concentrated solution, 5 percent IgG solutions are available (table 2).

•Large IVIG doses (1 to 2 grams/kg) should be divided into smaller doses given on different days, particularly in older adults.

Premedications — Premedications are not needed in all patients. Premedications may be useful for preventing reactions in individuals who have experienced specific reactions with previous administration. (See 'Anaphylaxis and anaphylaxis-like reactions' below and 'Headache and migraine (acute or delayed)' below.)

Our approach to deciding whether to use premedications is illustrated in the algorithm (algorithm 2) and includes the following:

●For individuals who have had a prior mild reaction with IVIG such as urticaria/hives, headache, chills, nausea, or myalgias, we suggest premedication. However, not administering premedication is also reasonable if the individual prefers. The specific combination of medications and their dosing is individualized; medications often include acetaminophen or a nonsteroidal antiinflammatory drug (NSAID), with or without diphenhydramine. Glucocorticoids are sometimes used, but we suggest avoiding these if possible, especially in individuals who are already immunosuppressed. These mild early reactions often subside with time, and the need for premedications should be revisited in individuals receiving regular infusions. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Premedications'.)

●Individuals who have tolerated previous IVIG infusions without a prior reaction are likely to tolerate subsequent infusions and generally do not require premedications.

●Practices vary for the first dose of IVIG (unknown whether a reaction will occur).

•Some clinicians prefer to avoid premedications with the first dose of IVIG, as this reduces the costs and time required to administer IVIG and avoids potential adverse effects from premedications that may not be necessary. Appropriate medications can be made available and can be taken if a mild reaction occurs.

•Other clinicians prefer to administer premedications to all individuals receiving a first dose of IVIG, as this may improve tolerability and avoid reactions in some cases. If the IVIG infusion is tolerated, the premedications can be omitted with subsequent infusions.

Further discussion of premedications is presented separately. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Premedications'.)

Change of products — Many strategies may be used to prevent or reduce infusion reactions, including reducing the rate of the infusion, switching to a different route (from intravenous to subcutaneous) if feasible, or providing premedications, as described above (see 'Premedications' above).

Changing products when a patient is tolerating infusions is generally avoided but may be tried when an individual is experiencing side effects if all other measures are unsuccessful. (See 'Strategies for reducing adverse events' above.)

Adverse effects may be more frequent and/or more severe whenever a new product is used. For this reason, extra caution and slow infusion rates should be used when changing the specific product used by any individual patient. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Infusion rates'.)

ANAPHYLAXIS AND ANAPHYLAXIS-LIKE REACTIONS

Overview of anaphylaxis and other immune reactions — Patients receiving IVIG may develop true anaphylaxis or reactions resembling anaphylaxis [20]. Anaphylaxis during IVIG administration is extremely rare, but it may be life-threatening [21]. The diagnosis is made clinically based on signs and symptoms (figure 1).

Anaphylaxis is a systemic reaction characterized by any combination of generalized hives, pruritus or flushing, angioedema (often of the face or lips), respiratory compromise, nausea or vomiting, or hypotension. (See "Anaphylaxis: Acute diagnosis", section on 'NIAID/FAAN diagnostic criteria'.)

Laboratory testing such as a serum tryptase level cannot be used to confirm or exclude the diagnosis of anaphylaxis rapidly enough to impact management; however, laboratory results from samples obtained at the time of the event can help to determine retrospectively if the reaction was anaphylaxis and may be useful for guiding future therapies. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

●True or suspected anaphylaxis – True or suspected anaphylaxis with hypotension and/or respiratory compromise is a medical emergency and should be treated rapidly with immediate discontinuation of the IVIG infusion and administration of intramuscular epinephrine and other therapies, which are delineated in rapid overview tables for children (table 3) and adults (table 4). (See "Anaphylaxis: Emergency treatment".)

True anaphylaxis is a rare (prevalence, 1 in 20,000 to 1 in 50,000), histamine-mediated reaction that can cause potentially life-threatening cardiovascular and/or respiratory compromise. The prevalence has likely decreased further with improved manufacturing processes. When it occurs, there appears to be an association between anaphylaxis mediated by anti-IgA antibodies in individuals with very low or absent IgA levels; however, larger studies are needed to evaluate such an association and to determine specific risk factors. Very low or absent IgA may be seen in individuals with IgA deficiency or common variable immune deficiency (CVID), and anti-IgA antibodies are typically of the IgE or IgG class (predominantly IgE) [22,23]. However, the role of anti-IgA antibodies in causing anaphylaxis in IgA-deficient patients receiving immune globulin therapy remains controversial [21]. IgG anti-IgA is common in IgA-deficient patients and often does not lead to anaphylaxis. Routine use of low IgA products is not necessary in all individuals with low IgA levels in the absence of an adverse event. Additional information about testing for anti-IgA is presented separately. (See "Selective IgA deficiency: Management and prognosis", section on 'Reactions to blood products'.)

Individuals with hypogammaglobulinemia due to nephrotic syndrome or protein-losing gastroenteropathy are far less likely to develop anti-IgA antibodies [20]. Anaphylactic reactions can occur in which IgE from the donor reacts with an antigen in the recipient, but these reactions are rare. (See "Immunologic transfusion reactions", section on 'Anaphylactic transfusion reactions'.)

●Other allergic and immune reactions – Urticaria, flushing, pain in the chest or lower back, nausea and/or vomiting, and/or a sense of impending doom or sudden anxiety are usually rate related and often occur midway through an IVIG infusion. Tachycardia and/or tachypnea may also be present. Various combinations of symptoms may occur.

It is important to check pulse, blood pressure, respiratory rate, and oxygen saturation prior to and during the infusion for any clinically significant changes. The infusion rate at the time the symptoms began to appear should be noted. If symptoms or other findings suggest a severe reaction, the infusion is stopped and the patient is treated accordingly. If symptoms are mild, the infusion may be held temporarily and restarted at a lower rate if symptoms resolve (eg, reduce the rate by 50 percent).

Reactions resembling anaphylaxis, such as those that include chest tightness, wheezing, and/or dyspnea, are more common than true anaphylaxis, and may be difficult to distinguish from true anaphylaxis at the outset. The subsequent course of the reaction and laboratory testing (eg, for IgE anti-IgA or tryptase) may allow categorization of these reactions. Unlike IgE-mediated anaphylaxis, these reactions are often accompanied by increases in blood pressure, rather than reductions. However, hypotension unrelated to an IgE-anti-IgA reaction may occur. Also, unlike true anaphylaxis, which may become more severe upon re-exposure to the antigen, these reactions tend to become milder with subsequent infusions.

The mechanism of anaphylaxis-like reactions is unknown. Possible contributing factors include complement activation by aggregates of IgG or immune complexes, reactions to active kinins or kallikrein in the IVIG product, secretion of prostaglandins or other eicosanoids in response to the IVIG, and/or release of cytokines in response to cross-linking of Fc-gamma receptors on lymphocytes.

●TRALI – Transfusion-related acute lung injury (TRALI) is a type of transfusion reaction characterized by the sudden onset of hypoxemic respiratory insufficiency during or shortly after transfusion of a blood product. The mechanism in patients receiving IVIG is likely to involve activation of neutrophils by anti-leukocyte/anti-HLA antibodies in the IVIG and/or rapid complement activation [24].

TRALI can cause respiratory distress similar to anaphylaxis, but TRALI is less likely to be associated with airway signs and symptoms such as stridor, cough, wheezing, and nasal congestion. TRALI does not cause urticaria, and gastrointestinal symptoms such as nausea and/or vomiting are uncommon.

Specific diagnostic criteria and management of TRALI are summarized in the tables (table 5 and table 6) and discussed separately. (See "Transfusion-related acute lung injury (TRALI)", section on 'Blood component risk factors'.)

Management and future prevention

Preparation — Medications and resuscitation equipment should be immediately available to treat anaphylaxis in all individuals, especially those known to be IgA-deficient. Many clinicians prefer to administer the initial dose in a monitored setting. In some countries, including the United States, patients are often prescribed epinephrine autoinjectors when IVIG is administered at home.

●Emergency treatment – If anaphylaxis with hypotension occurs, rapid treatment should be initiated with intramuscular epinephrine and other therapies as described in the rapid overview tables for children (table 3) and adults (table 4). (See "Anaphylaxis: Emergency treatment".)

●Testing for anti-IgA – We do not routinely measure anti-IgA antibodies in patients with IgA deficiency prior to giving an IVIG infusion, because the majority of patients with IgA deficiency tolerate IVIG products, including those with anti-IgA [21].

However, testing is reasonable in those who have had an anaphylactic or a possible anaphylactic reaction and are expected to require additional infusions of IVIG or blood transfusions in the future. The particle gel immunoassay method is reliable and rapid [25]. Anti-IgA testing (especially for IgG anti-IgA) is available from several academic and commercial laboratories.

If testing is not available, switching to subcutaneous immune globulin (SCIG) or a low IgA product is reasonable, in addition to using premedications, depending on the severity of the reaction.

●Preventive strategies for future infusions – Various approaches can be considered to reduce the risk of anaphylaxis in the future. Strategies to reduce the risk of future reactions include the following:

•Switching to a SCIG product for individuals receiving lower doses of IgG (eg, for primary or secondary immunodeficiency). SCIG is often tolerated, even in individuals with anti-IgA antibody [26]. The reason for reduced reactions to SCIG products is unclear, as these products contain IgA; it may involve induction of tolerance, as discussed separately. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'IgA-deficient patients'.)

•Switching to an IVIG product with low IgA content [26]. The available products vary widely in IgA content, ranging from less than 1 mcg/mL to greater than 600 mcg/mL (table 2). The individual should receive pretreatment or concomitant treatment with antihistamines and/or glucocorticoids. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Premedications'.)

•Some clinicians administer premedications to individuals with IgA deficiency who have not had a previous reaction, and if the initial infusion is tolerated, the premedications can be reduced gradually with subsequent infusions.

•For individuals with a previous anaphylactic reaction who receive another IVIG product, it is prudent to use an initially slow rate of administration (eg, 0.001 mL/kg/minute), giving a test dose first with 1 mL and then with 10 mL. If the patient tolerates the initial infusion, the rate of administration for the remainder of the product can be increased. If a winged infusion set (butterfly needle) is being used, it is also prudent to secure IV access with a separate line, in case fluids or additional medications are needed to manage a recurrent reaction.

●Evidence – The evidence linking anti-IgA antibodies with anaphylaxis to IVIG is weak, and pathophysiology of these reactions remains controversial [20,21,27]. In principle, the immune system of an individual with serum IgA levels that are undetectable or <5 to 7 mg/dL could recognize IgA in the IVIG product as a novel or foreign antigen and produce anti-IgA. Among patients with very low or undetectable serum IgA, anaphylaxis is more likely in disorders in which other antibody production is still possible.

In contrast, anaphylaxis is less likely in individuals with partial IgA deficiency (low but detectable levels of circulating IgA), since IgA would not appear as a novel antigen, although these patients may have other serious reactions to blood or plasma products. Anaphylaxis is not usually a concern in patients with X-linked (Bruton's) agammaglobulinemia, because those patients cannot make antibodies at all or only to a very limited degree. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis".)

When present, anti-IgA antibodies may be of the IgG or IgE class; IgG is more commonly identified and may activate basophils [23,28-30]. A 2017 review evaluated 23 reports of anaphylaxis associated with anti-IgA antibodies of the IgG class, and three reports of anaphylaxis associated with IgE antibodies to IgA [20]. These were the only reported cases from the 1960s to the time of publication. The prevalence of these antibodies was particularly high in patients with the combination of IgA and IgG2 subclass deficiency (ie, 29 percent), yet most patients with anti-IgA antibodies tolerate IVIG without incident, even products that are not specifically designated as low in IgA. A 2012 review of the literature identified 49 patients with IgA deficiency and IgG anti-IgA who tolerated IVIG [21].

Patients who do not have true anaphylaxis — It may be determined in retrospect that an individual had a reaction that was not true anaphylaxis, supported by one or more of the following findings:

●Hypertension rather than hypotension

●Urticaria that did not progress to true anaphylaxis

●Meeting criteria for TRALI (table 6)

●Serum IgA testing revealing presence of IgA

Normal serum tryptase is consistent with a non-anaphylactic reaction but cannot be used to exclude anaphylaxis; some individuals with true anaphylaxis have a normal tryptase level. The sensitivity and specificity of this testing are not well-established, and the test needs to be done as soon as possible after the reaction (within 15 minutes and up to three hours), as discussed separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Tryptase'.)

Clinicians may delay testing of IgA levels following IVIG infusion so as not to mistake IgA from the product as the patient's IgA (a theoretical concern). For most individuals with immunodeficiency, the information will already be available.

In individuals who are established to have an allergic, nonanaphylactic reaction, symptoms such as urticaria often diminish with subsequent infusions. It may be possible to temporarily stop the infusion, treat with an antihistamine and/or glucocorticoids and continue the infusion if symptoms resolve, as long as prior similar reactions have been determined not to be true anaphylaxis based on the findings listed above. (See "Immunologic transfusion reactions", section on 'Allergic reactions'.)

Other clinicians or patients may prefer to use strategies identified for true anaphylaxis, such as switching to an SCIG product, out of an abundance of caution. (See 'Preparation' above.)

In individuals who are determined to have TRALI rather than anaphylaxis, the implicated IVIG product is not used for future infusions; the reaction is not expected to recur with subsequent IVIG. (See "Transfusion-related acute lung injury (TRALI)", section on 'Prevention'.)

OTHER IMMEDIATE REACTIONS — Immediate reactions are those that happen during or within six hours of the IVIG infusion; these represent 60 percent of adverse IVIG reactions [2]. Systemic reactions during the infusion are especially common in patients receiving their first infusion of IVIG, changing to a different IVIG product, or resuming treatment after missing several doses.

Potential immediate reactions include rate-related reactions in individuals with or without a concurrent infection or a non-IgE-mediated allergic reaction due to an immune mediator in the product or elicited by the product. These reactions are rarely serious, but they can be distressing to the patient.

Local reactions at the administration site (eg, pain, bleeding, bruising) are less common with IVIG, compared with either subcutaneous immune globulin (SCIG) or intramuscular immune globulin (IMIG) [2].

Simply stopping the infusion until symptoms subside spontaneously and/or have been treated may be sufficient management in many cases. In most instances, the infusion may then be restarted at a lower rate. Severe reactions require subsequent supervised infusions.

The different types of immediate reactions, as well as preventive measures and treatments, are discussed in this section and summarized in the table (table 1).

Pain or systemic (influenza-like) symptoms — Pain or systemic symptoms can be due to phlogistic reactions; these include generalized inflammatory symptoms that may accompany the use of IVIG, especially in patients with an acute infection. This may be more likely in patients with an underlying immunodeficiency that puts them at risk of bacterial infections. Often, the reaction occurs in the setting of a chronic sinus or pulmonary infection. Symptoms may be especially pronounced if the infection has not been treated with antibiotics and the patient is receiving IVIG for the first time.

Symptoms may resemble those that accompany the onset of infection in individuals with intact immune function. Examples include chills (and even rigors), fever, flushing, myalgias (eg, back pain), arthralgias, malaise, nausea, vomiting, and/or headache [31].

These symptoms are thought to result from interactions of the newly delivered antibodies with bacterial antigens, neoantigens in the patient, or pathologic autoantibodies in the patient. Bacterial lipopolysaccharide (LPS) or other products released from newly opsonized organisms may also stimulate toll-like receptors and activate leukocytes and macrophages leading to rapid release of cytokines and/or eicosanoids.

When possible, patients with immunodeficiency should have a thorough search for any occult infections and should receive appropriate antibiotics if an infection is identified, before receiving IVIG. In such cases, a one to two day delay in administering IVIG is appropriate, provided the infection is resolving (absence of severe fever or other acute symptoms). However, the initiation of IVIG should not be delayed for longer than one to two days in patients who have an infection that has not responded to routine antimicrobial therapy. (See "Immune globulin therapy in inborn errors of immunity", section on 'Initial doses and schedules'.)

The inflammatory symptoms may be minimized by giving the IVIG slowly and/or premedicating with antipyretics and/or glucocorticoids, as described above. (See 'Strategies for reducing adverse events' above.)

If symptoms occur despite a delay in IVIG administration, management generally involves temporarily interrupting the infusion and/or treating specific symptoms.

●Flushing, gastrointestinal symptoms, headache, back pain, and chest pain may be treated with a nonsteroidal antiinflammatory drug (NSAID) or acetaminophen. Aspirin should be avoided in children.

●More severe back or chest pain may require opioid analgesics, but opioids are rarely needed.

●Diazepam or meperidine may be used for rigors, muscle spasm, or severe musculoskeletal pain.

However, clinicians should be aware that high-quality evidence to support this practice is lacking.

Treatment of nausea and vomiting is discussed separately. (See "Approach to the adult with nausea and vomiting", section on 'Treatment'.)

Headache and migraine (acute or delayed) — Headache is a common side effect of IVIG in children and adults. This was illustrated in a prospective study that evaluated adverse effects resulting from 345 IVIG infusions in 58 children [9]. Headache was the most common adverse event, often lasting more than a day and sometimes resulting in absence from school.

●Headache at the time of the infusion – Additional preventive measures may include the following:

•Administration of IVIG at a slower rate

•Adequate hydration

•Premedication

-For any type of headache, diphenhydramine or a second-generation antihistamine can be used.

-For those with a history of migraine-like symptoms, cyproheptadine may be used. Cyproheptadine is an antihistamine and serotonin receptor antagonist that can be given at a dose of 2 to 4 mg for children or 4 to 12 mg for adults and repeated at the first sign of symptoms.

Patients with a history of migraine can also premedicate with other types of antimigraine preparations [32]. (See "Preventive treatment of migraine in children" and "Preventive treatment of episodic migraine in adults".)

If anti-migraine therapies are ineffective in preventing symptoms, premedication with a glucocorticoid may be used. Examples include prednisone or prednisolone at a dose of 0.5 to 1 mg/kg or equivalent in divided doses in children, or 30 to 60 mg in adults. Intravenous hydrocortisone may also be used, at a dose of 2 mg/kg in children or 50 mg in adults.

-For post-infusion headaches accompanied by fever and/or signs of meningismus, premedication with a glucocorticoid may be tried, since these findings may be triggered by immunologic reactions within the central nervous system. In some cases, one or more of these medications may be required for as long as 72 hours after the infusion is completed. However, glucocorticoids do not appear to be useful in treating aseptic meningitis induced by IVIG [33]. (See "Acute treatment of migraine in adults" and "Acute treatment of migraine in children" and "Aseptic meningitis in adults".)

In many patients, headaches diminish after the first few infusions, although some individuals develop a recurrent pattern of symptoms occurring at seemingly reproducible intervals after each infusion. If headaches do not diminish, switching to more frequent, smaller doses of SCIG may also be helpful (if appropriate for the underlying disorder).

●Delayed headache – A small percentage of patients develop more serious headaches, particularly those with a history of migraine or those receiving high doses of IVIG (eg, 1 to 2 g/kg) for autoimmune diseases, such as immune thrombocytopenia (ITP) [15,34]. These more significant headaches may be delayed by as much as 48 to 72 hours following the infusion and may be accompanied by photophobia, nausea and vomiting, and/or other symptoms of migraine [35]. As noted above, a two- to three-day course of a glucocorticoid may be needed in some cases.

The delay reported between the end of the IVIG infusion and the onset of severe headache may suggest that these more severe headaches may be related to immunologic reactions that develop as the exogenous antibodies enter the central nervous system. Nuchal rigidity and/or other signs of meningismus may also be present as well as fever, suggesting that there is a continuum of symptoms, extending to include aseptic meningitis with pleocytosis. The evaluation for possible meningitis is presented separately. (See "Aseptic meningitis in adults".)

The mechanism of severe IVIG-associated headache is incompletely understood, and there may be many possible causes.

In one study of patients receiving 2 g/kg of IVIG for neuromuscular diseases, 11 percent developed severe headache accompanied by other signs suggesting aseptic meningitis, a rate much higher than that in most studies [15]. Five of these patients subsequently underwent lumbar puncture within 48 hours, which showed neutrophilic pleocytosis in four and increased cerebral spinal fluid (CSF) IgG concentrations in all five. Headaches were not prevented by changing the brand of IVIG, fractionating the dose, or administering glucocorticoids. This study suggests that some of the severe headaches may be due to meningeal irritation and/or inflammation caused by antibody-antigen reactions or by the IgG itself.

Volume overload (TACO) — Transfusion-associated circulatory overload (TACO) is a syndrome of pulmonary edema due to volume overload. This is more likely to occur in patients with preexisting cardiac or renal disease, particularly because of the high volume of IVIG used to treat autoimmune disorders (in the range of 1 to 2 grams/kg daily dose). Approximately 10 mL of fluid is administered per gram of IVIG.

Signs and symptoms include dyspnea, orthopnea, headache, tachycardia, and/or hypertension. Evaluation and management are discussed separately. (See "Transfusion-associated circulatory overload (TACO)".)

Risk for volume overload should be determined prior to each IVIG infusion, and diuretics can be used for patients with increased risk. For individuals who have experienced signs and symptoms of volume overload with IVIG, future infusions can be given more slowly with diuretics. Preparations that are more concentrated or have lower salt content may be used. SCIG is another option.

TRALI — Transfusion-related acute lung injury (TRALI) is a transfusion reaction that causes acute respiratory distress; it may initially be challenging to distinguish from TACO, although certain features such as fever or hypotension may be helpful in differentiating TRALI from TACO (table 7).

Evaluation, management, and pathophysiology are discussed separately. (See "Transfusion-related acute lung injury (TRALI)".)

TRALI is thought to be product-specific, and the manufacturer should be notified of the reaction and lot number. Subsequent infusions of other products or lot numbers are not expected to cause additional reactions.

DELAYED REACTIONS — Some adverse events can occur during the infusion or a few days afterwards; these represent approximately 40 percent of all adverse reactions to IVIG [2]. These include thromboembolic events or complications affecting the kidney or blood cells (table 1).

Thromboembolic events — Thromboembolic events may accompany or follow IVIG infusions, and prescribing information for all IVIG products includes a Boxed Warning about this risk [36]. The frequency of these events is likely to depend on the dose and infusion rate of IVIG, the underlying indication, and patient-related factors such as immobility.

Because of the association between IVIG and thromboembolic events, the placement of indwelling intravenous catheters solely for the purpose of administering IVIG is not recommended.

●Risk factors – The risk of thromboembolic events is of particular concern when high-dose therapy (≥1 g/kg) is used and administered rapidly. In a case-control study that compared 19 individuals who experienced a thromboembolic event with 38 age-matched controls (median age, 71 years), a trend towards increased thromboembolic risk that did not reach statistical significance was suggested if two or more cardiovascular risk factors (smoking, coronary artery disease, cerebrovascular disease, diabetes, hypertension, hyperlipidemia) were present (odds ratio [OR] 1.3, 95% CI 0.45-4.30); this increased risk became statistically significant when four or more of these risk factors were present (OR 10.5; 95% CI 1.91-57.58) [16].

Other data suggest that hereditary hypercoagulable states, hyperviscosity, malignancy, indwelling catheters, autoimmunity or connective tissue disease, older age, estrogen use, previous thrombotic events, and immobilization may also increase risk [2]. Hyperviscosity may occur with dehydration, syndromes such as cryoglobulinemia or monoclonal gammopathies, or human immunodeficiency virus (HIV) infection; hyperviscosity may also be due to components of the IVIG product itself (sugars, osmotically active stabilizers, immunoglobulins) [16,37-40]. In a series of 2724 first-time IVIG infusions in patients with chronic lymphocytic leukemia (CLL) or multiple myeloma, the incidence of arterial embolic events was increased during the first day (from a baseline of 1.8 percent to 2.5 percent) [17]. Patients with no identified risk factors may also develop thromboembolic complications [41].

The US Food and Drug Administration (FDA) worked with an IVIG manufacturer to incorporate steps to reduce the levels of procoagulant factors, after clotting factors were suggested to be implicated in some thromboembolic events in the past [14,42].

●Sites – Sites of thrombosis may be arterial (in approximately 80 percent) or venous, and include acute coronary syndrome, myocardial infarction, transient cerebral ischemia attack, stroke, deep vein thrombosis, and pulmonary embolism [41,43-49]. Local thrombosis at the site of IVIG infusion can also occur, with extension from the extremity to larger veins [50-52].

●Timing – Timing of thromboembolic events is variable. In one series from a neurology center in which 62 patients were treated with a total of 616 courses of IVIG over two years, thromboembolic events occurred in seven patients (11 percent) [53]. In five patients, the event occurred within two weeks of treatment. This rate is somewhat higher than the overall background rate of approximately 0.8 events per 1000 kg of IVIG distributed, or 1 event per 10,000 courses of 100 grams [54]. Other reports suggest arterial events are more likely to occur within hours to days of an infusion, whereas venous events are more likely to occur after days to weeks [2].

●Prevention – The risk of thromboembolism can be minimized by ensuring adequate hydration and avoiding prolonged immobilization (eg, airplane travel) in the days following the infusion. Additional strategies in patients at high risk of thromboembolic complications include the following:

•Avoid administration of large doses in a single day; doses can be divided such that no more than 500 mg/kg is administered per day.

•Administer IVIG at relatively slow rates, such as below 3000 mg/hour or 50 mg/kg/hour and avoid "as-tolerated" dose escalations [55].

•Use products with a lower osmolarity for patients at risk of hyperviscosity (table 2).

•Assess blood viscosity in patients with hyperviscosity syndromes. Patients are most likely to become symptomatic at viscosities in excess of 5 to 8 centipoise. In patients with values higher than this, it may be prudent to consider plasmapheresis to lower the viscosity prior to administering IVIG. However, this approach has not been formally studied.

Complications affecting the kidney — Prescribing information for all IVIG products includes a Boxed Warning about the risks of acute kidney injury (AKI), osmotic nephrosis, and death from kidney dysfunction. Additional complications such as hyponatremia can also occur.

Acute kidney injury — AKI (abrupt decline in glomerular filtration rate) is a rare complication of IVIG that is estimated to occur with less than 1 percent of infusions [56].

Risk factors for AKI from IVIG include [56]:

●Age greater than 65 years

●Preexisting chronic kidney disease (CKD; creatinine clearance <60 mL/min)

●Diabetes mellitus

●Higher doses of IVIG

●Hypovolemia

●Concomitant use of nephrotoxic agents

●Very high titers of rheumatoid factor

Clinical manifestations vary from an asymptomatic rise in the plasma creatinine concentration to anuria. Spontaneous resolution typically occurs within 4 to 10 days after IVIG is discontinued [56]. However, permanent kidney failure has been reported. AKI has mostly occurred with IVIG products containing sucrose and led to the discontinuation of these products, although other stabilizing agents have been implicated as well [57,58].

The pathogenesis is believed to involve an osmotic mechanism, similar to that of "sucrose nephropathy," in which sugar is taken up by tubular cells and the increased solute load causes the cells to become vacuolated, swell, and obstruct the tubules, creating a histopathologic lesion referred to as osmotic nephrosis [59-62]. Additional mechanisms that may apply in some patients include renal heme pigment injury related to hemolysis, increased blood viscosity, and immune complex deposition [63].

Strategies to minimize the risk of AKI include ensuring adequate hydration prior to starting the infusion and avoiding administration of large doses in a single day; doses can be divided such that no more than 500 mg/kg is administered per day (table 2) [4].

Hyponatremia — Hyponatremia is a rare complication of IVIG that can occur in individuals with underlying CKD or those who develop AKI from the IVIG therapy [64]. The mechanism is dilutional and is thought to involve the inability of the kidney to handle the free water load in the setting of an underlying defect in free water excretion. Free water comes from the IVIG solution as well as from translocation of water from the intracellular to the extracellular compartment as a result of high concentrations of maltose in one IVIG solution [65-67].

It is important to distinguish true hyponatremia, which is associated with decreased serum osmolality, from pseudohyponatremia, which is a laboratory artifact (see 'Laboratory abnormalities that do not require evaluation' below), because patients with pseudohyponatremia should not have free water restriction, which in turn could increase the risk of other complications of IVIG [68].

A clue to pseudohyponatremia is a concomitant normal serum osmolality [69]. Distinction between true hyponatremia and pseudohyponatremia using measurement of serum osmolality is presented separately. (See "Diagnostic evaluation of adults with hyponatremia".)

Management of hyponatremia is also presented separately. (See "Overview of the treatment of hyponatremia in adults".)

Hematologic complications — Hematologic complications of IVIG include hemolysis and neutropenia; these are usually transient.

Hemolysis — Clinically significant hemolytic anemia has been reported after IVIG infusion [1,63,70-77]. The mechanism involves passive transfer of antibodies present in the IVIG product, referred to as isoagglutinins, that react with red blood cell (RBC) antigens, predominantly of the ABO blood group system (anti-A and anti-B). In mild cases, an antibody may be demonstrated as a positive direct antiglobulin (Coombs) test (DAT), although this is not always seen because antibody-sensitized RBCs may be cleared rapidly.

Confirmatory testing requires demonstration that the antibody is reactive with blood group A or B cells in the eluate. (See "Pretransfusion testing for red blood cell transfusion", section on 'Antibody screen'.)

Mild hemolysis with IVIG infusions may result in transient anemia with reticulocytosis. Intravascular hemolysis may manifest with a decreased serum haptoglobin level and increased lactate dehydrogenase (LDH), and acute severe intravascular hemolysis can cause hemoglobinemia, hemoglobinuria, and kidney damage/dysfunction.

Product-related risk factors for hemolysis include high-dose infusions (1 to 2 grams per kg per day), high IVIG doses (eg, >100 grams), female sex, and non-O blood group [63,78-80]. This was illustrated in a series of 1000 patients receiving IVIG in which 16 cases of hemolysis were identified (1.6 percent) [78]. Factors present in more than half the patients with hemolysis included a large dose of IVIG, non-O blood group, increased inflammatory markers such as increased erythrocyte sedimentation rate (ESR), and female sex. The onset of hemolysis ranged from 12 hours to 10 days, and the mean decrease in hemoglobin was 3.2 g/dL. Some primary immune deficiencies are associated with increased risk of autoimmune hemolytic anemia (AIHA). (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency", section on 'Cytopenias'.)

We usually suggest testing for hemolysis five to seven days after the infusion. The hemolytic screen includes DAT, hemoglobin level, reticulocyte count, haptoglobin, and LDH (table 8) for patients receiving high-dose infusions and non-O blood group as well as individuals who have had a prior episode of hemolysis associated with IVIG or prior evidence of an anti-A and/or anti-B antibody. A positive antiglobulin test following the infusion is evaluated by testing for antibody specificity and hemolysis and addressed as appropriate (see "Diagnosis of hemolytic anemia in adults", section on 'Diagnostic approach'). If IVIG is being used to treat a condition responsible for hemolysis, then the infusion should proceed with caution.

Some manufacturers have been developing additional steps in the manufacturing process such as immunoaffinity chromatography that decrease isoagglutinins [81,82]. When applied to the Privigen product (table 2), this resulted in an approximately 90 percent reduction in isoagglutinins, without apparent effect on product quality [82,83]. Donor screening for anti-A and anti-B may also be used.

For patients with clinically severe hemolysis and a positive anti-A and/or anti-B antibody due to IVIG, we would avoid re-administering a product with the same lot number. Switching brands of IVIG may be helpful [76]. (See "Pretransfusion testing for red blood cell transfusion", section on 'Compatibility testing (crossmatch)'.)

When appropriate, subcutaneous immune globulin (SCIG) may also be substituted as almost all cases of hemolysis are associated with the high doses given by the intravenous route of administration, with only rare reports of hemolysis associated with subcutaneous administration [76].

If anemia resulting from hemolysis due to anti-A and/or anti-B is severe enough to require transfusion, it is recommended to transfuse group O RBCs, to avoid the possibility of further hemolysis [84]. Discussion with the transfusion medicine service or blood bank is advised. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Washed red cells'.)

Neutropenia — Neutropenia is a rare complication of IVIG, and we do not routinely evaluate for neutropenia following IVIG infusion. However, we do obtain a complete blood count (CBC) as part of monitoring for hemolysis. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Monitoring'.)

Neutropenia may be appreciated in patients being evaluated for transfusion-related acute lung injury (TRALI) or a possible infection [85-87]. If a patient develops neutropenia in the setting of TRALI, the specific product would not be given again to that recipient, and the product would be reported to the blood bank or to adverse event reporting through the manufacturer. (See "Transfusion-related acute lung injury (TRALI)".)

Neutropenia associated with IVIG may be due to neutrophil margination to the vascular wall upon activation by complement or immune globulins in the IVIG product. Another mechanism involves immune clearance induced by antineutrophil antibodies or antibodies to "sialic acid-binding Ig-like lectin 9" (Siglec-9) in IVIG [88,89]. In some cases, neutropenia may be a feature of an underlying immunodeficiency rather than a complication of the IVIG. In most instances, neutropenia is transient, and intervention is not required [87,90,91].

LATE REACTIONS — Adverse events that may occur weeks to months after receiving IVIG include dermatologic reactions, impaired vaccination response, and the theoretical (but highly unlikely) risk of an infectious agent transmitted from the IVIG product.

Other reactions possibly related to IVIG include case reports of necrotizing enterocolitis in premature infants, ileitis in adults, uveitis, hypothermia, non-infectious hepatitis, and serum sickness with arthritis [2].

Dermatologic reactions — Eczematous dermatitis associated with IVIG therapy has been described in 64 cases, mostly in patients receiving high doses for neurologic diseases [92]. This often occurs in patients with preexisting dermatologic disease. A vesicular eruption of the palms or soles (dyshidrotic eczema), appearing within eight days of administration, was a characteristic presentation. Most patients were successfully treated with topical corticosteroids, with resolution within three weeks. However, reactions tended to recur with subsequent IVIG treatments, requiring ongoing therapy. A few cases of alopecia, erythema multiforme, and baboon syndrome have been reported [2]. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)

Effects on vaccine efficacy — IVIG can impair a patient's response to live virus vaccines, which must replicate in the host to deliver an immunogenic antigen load. Thus, the timing of some vaccinations, particularly against measles, mumps, and rubella, may need to be changed to achieve optimal immunization.

An annual inactivated influenza vaccine is recommended for most patients; this should not interfere with or interrupt IVIG administration.

Patients who require vaccination with certain live-virus vaccines (eg, measles vaccine) should follow appropriate recommendations regarding the timing of administration relative to the IVIG (table 9). This is because antibodies present in the IVIG may interfere with the normal immune response to the vaccine and hence reduce vaccine efficacy. (See "Vaccination for the prevention of chickenpox (primary varicella infection)", section on 'Recent receipt of immune globulin or blood' and "Measles, mumps, and rubella immunization in infants, children, and adolescents", section on 'Recent receipt of blood or immune globulin'.)

If supplies of a critical vaccine are limited and the vaccine is available, it can be administered without delay. If there is less urgency, it may be prudent to give a vaccine two weeks before or after the IVIG, primarily to allow distinction between adverse reactions to the vaccine versus the IVIG. This recommendation is consistent with guidance from the Australasian Society of Clinical Immunology and Allergy related to coronavirus disease 2019 (COVID-19) vaccination [93].

Infectious risks — The manufacturing process of available IVIG products reduces the risk of transmission of viruses and prions. No product produced with current safety measures has ever been reported to have transmitted a bloodborne disease, and no transmission of Creutzfeldt-Jakob disease or other human prion-mediated disorder has been reported in any patient receiving IVIG. No cases of HIV infection have been reported. One cannot be certain that available measures will remove or inactivate all potential (and as yet undescribed) clinically significant pathogens.

Parvovirus B19 is not destroyed by solvent detergent or heat treatment; however, it is thought that antibodies to parvovirus present in the IVIG preparations are sufficient to prevent clinical infection [2].

Despite the safety of available IVIG products, historical cases of infectious transmission have been reported. As an example, during a six-month period in 1994, 112 cases of hepatitis C virus (HCV) infection associated with the use of IVIG were reported to the United States Centers for Disease Control [94]. Additional cases were reported in Europe [95]. Steps were subsequently added to the plasma procurement and IVIG processing procedures to reduce risks of transmission of bloodborne pathogens.

Further measures taken by the manufacturer include the following:

●All plasma is derived from United States donors (for products used in the United States).

●Plasma donors must complete a detailed questionnaire about risk factors and possible exposures. (See "Blood donor screening: Overview of recipient and donor protections".)

●Each unit of donated plasma is tested for known viruses by antigen and nucleic acid testing (NAT; eg, polymerase chain reaction); and for elevations of hepatic transaminases, which may alert the laboratory of a viral infection not detected by available assays. (See "Blood donor screening: Laboratory testing".)

●Donated units of plasma that pass these tests are then subject to quarantine until a subsequent donation from the same donor has been obtained, tested, and found to be free of pathogens. Only then can the previous donation be pooled. NAT is then repeated as the units of plasma are pooled.

●Each manufacturer must employ multiple complementary purification and virus inactivation/removal steps in the production process. These include ethanol or polyethylene glycol (PEG) precipitation, caprylate and/or other fatty acid treatment, depth filtration, and chromatography steps, which result in multiple log fold reductions of test viruses (table 2). These are combined with additional steps specifically intended to inactivate viruses, such as solvent/detergent treatment or pasteurization (prolonged treatment at 60°C), which destroy the envelopes of viruses such as HCV, HIV, and West Nile virus [96,97]. Nanofiltration, also termed "virus filtration," is performed with several products to remove nonenveloped viruses.

●Additional quality control is performed by testing the recovery of animal pathogens that are introduced into test lots of IVIG products (which are used only for testing and are not administered to patients) [97-99]. These procedures have been shown to inactivate or remove the following animal pathogens:

•Bovine diarrhea virus, an enveloped RNA virus that serves as a model for HCV.

•Pseudorabies, a large, enveloped DNA virus that serves as a model for human herpes-family viruses.

•Reovirus, a nonenveloped RNA virus.

•A porcine parvovirus that serves as a model for human parvovirus B19.

•Rodent-adapted hamster scrapie, a model for prion diseases.

In addition, recommendations for improved record keeping and monitoring of patients have been developed [100]. The dose, brand, lot number, expiration date, and manufacturer of any immune globulin product infused into any patient should be recorded in the medical record, as done for blood products. Furthermore, patients should be encouraged to keep their own logs of this information. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Monitoring'.)

LABORATORY ABNORMALITIES THAT DO NOT REQUIRE EVALUATION — IVIG has a variety of transient effects on laboratory tests that are generally considered not to be clinically important and should not be investigated in the absence of concerning symptoms. However, it may be helpful to be aware of these changes to avoid an extensive evaluation and/or interventions.

●Viscosity/ESR – IVIG increases serum viscosity and may alter the erythrocyte sedimentation rate (ESR) [38].

●Sodium – Pseudohyponatremia can also be seen due to IVIG administration [68,101,102]. This phenomenon is due to the protein load, which increases the nonaqueous phase of plasma. Because the concentration of sodium is physiologically regulated in the aqueous phase, but the laboratory sodium determination uses the total plasma volume of the sample, an artifactual dilution of sodium results. (See "Causes of hypotonic hyponatremia in adults".)

Patients with underlying kidney disease may develop true hyponatremia, as discussed above. (See 'Hyponatremia' above.)

●Osmolality – Maltose accumulation can also lead to an osmolal gap, as the measured plasma osmolality is greater than that estimated from the contributions of sodium, potassium, glucose, and urea. Affected patients are not at risk for symptoms of hyponatremia, since the plasma osmolality is modestly increased, not reduced. Maltose may also give false readings with glucose meters that use test strips containing glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ) or glucose-dye-oxidoreductase (GDO) [103].

●Serologies – Serologic tests for various antibodies (especially antiviral titers, but possibly also antinuclear antibodies [ANA], antineutrophil cytoplasmic antibodies [ANCA], rheumatoid factor) may become falsely positive due to the passively transmitted antibodies in IVIG. These serologic tests are unreliable following an infusion since it is difficult (unless the patient has agammaglobulinemia) to determine if the patient or the donor pool is the source of the antibodies. Since the half-life of IgG is 21 to 28 days, this effect should not persist beyond 60 days, and it should not affect assays for IgM or IgA antibodies. Polymerase chain reaction testing for specific viruses can be helpful in distinguishing passively transferred antibodies from prior infection in some settings.

●Coombs – A positive direct antiglobulin (Coombs) test (DAT) without clinically apparent hemolysis may be seen transiently in as many as 30 percent of patients receiving high-dose IVIG. Evaluation of a newly positive DAT is discussed above (see 'Hemolysis' above). However, a known positive DAT, especially if associated with the patient's underlying condition, does not require further intervention if there is no evidence of hemolysis.

●Beta-D-glucan – Some IVIG products may cause false-positive results on the beta-D-glucan assay, a test for the detection of systemic aspergillus. (See "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)

SUMMARY AND RECOMMENDATIONS

●Risk factors – Adverse reactions occur with up to 5 to 15 percent of all intravenous immune globulin (IVIG) infusions and affect 20 to 50 percent of individuals receiving IVIG. Risk factors include those related to the product (higher doses, faster infusion rates) and the patient's underlying condition (hyperviscosity states, organ dysfunction, and/or prothrombotic stimuli). Anaphylactic reactions due to anti-IgA in individuals with IgA deficiency are extremely rare. Reactions are most likely to occur during the first infusion or after changing brands. (See 'Incidence and risk factors' above.)

●SCIG versus IVIG – Systemic reactions to subcutaneous immune globulin (SCIG) are much lower than to IVIG, with the exception of local reactions such as pain, swelling, and redness at the infusion sites, which are more common with SCIG. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'Comparison of SCIG with IVIG'.)

●General strategies – General strategies for minimizing the risk of adverse reactions to IVIG include ensuring adequate hydration, treating infections before initiating therapy, starting with a slow infusion rate, and avoiding substitution of another brand once a well-tolerated preparation has been identified (table 1). Some clinicians give the first dose in the hospital, especially for individuals with known risk factors. (See 'Strategies for reducing adverse events' above.)

●Premedications – Individuals who have not had a prior reaction are likely to tolerate subsequent infusions, and we generally omit premedications (algorithm 2). For individuals who have had a prior reaction to IVIG, we suggest premedication to reduce recurrence of the reaction (Grade 2C). The premedications and doses are individualized. (See 'Premedications' above.)

●Anaphylaxis – Anaphylaxis to IVIG is extremely rare but may be life-threatening. Many clinicians administer the initial dose in a monitored setting. The diagnosis is made clinically; laboratory testing (levels of anti-IgA, serum tryptase) can be obtained for later review. The cause is often an IgA-deficient individual with anti-IgA antibodies (predominantly IgE) that can react with IgA in the infused product. However, most IgA-deficient individuals tolerate IVIG without difficulty, and low levels of IgA (as opposed to undetectable levels) are not considered a risk factor for anaphylaxis. (See 'Anaphylaxis and anaphylaxis-like reactions' above.)

Treatment of anaphylaxis is outlined in tables for children (table 3) and adults (table 4) and discussed separately. (See "Anaphylaxis: Emergency treatment".)

For individuals with true anaphylaxis due to anti-IgA, avoidance of future IVIG is ideal, but if not possible, switching to SCIG or using a product with the lowest amount of IgA (table 2) are reasonable alternatives. Pretreatment with antihistamines and/or glucocorticoids and giving the initial infusion at a very slow rate are also useful. (See 'Preparation' above.)

●Allergic reactions – For those with allergic symptoms that in retrospect are determined not to be true anaphylaxis, subsequent infusions are generally tolerated with diminution of symptoms. Use of premedications is individualized based on the severity of the reaction and clinician and patient preferences. (See 'Patients who do not have true anaphylaxis' above.)

●TRALI – Transfusion-related acute lung injury (TRALI) does not tend to recur if the implicated product is avoided. (See "Transfusion-related acute lung injury (TRALI)".)

●Inflammatory reactions – Inflammatory (phlogistic) reactions including pain, systemic symptoms, and headache are managed symptomatically (table 1). Bacterial infections should be identified, and treatment initiated, before the first dose of IVIG. Individuals with a history of headache with IVIG can receive premedication with antihistamines or anti-migraine therapies if there is a history of migraines. (See 'Pain or systemic (influenza-like) symptoms' above.)

●Volume overload (TACO) – Volume overload is managed using slower infusions, products with lower salt concentrations, and diuretics. (See 'Other immediate reactions' above.)

●Thrombosis – Thromboembolic events (myocardial infarction, stroke, venous thromboembolism) may accompany or follow IVIG infusions, and prescribing information for all IVIG products includes a Boxed Warning about this risk. We avoid placing indwelling intravenous catheters solely for the purpose of administering IVIG. Other strategies to minimize these events include ensuring adequate hydration, avoiding prolonged immobilization, spacing large doses over several days, and slowing infusions. For individuals with a history of thromboembolic events related to IVIG, low osmolarity products may be used. (See 'Thromboembolic events' above.)

●Acute kidney injury (AKI) and hyponatremia – Complications affecting the kidney may accompany or follow IVIG infusions, and prescribing information for all IVIG products includes a Boxed Warning about these risks. Strategies to minimize AKI include ensuring adequate hydration and avoiding more concentrated products in those with underlying kidney disease (table 2). Hyponatremia can also occur and must be distinguished from pseudohyponatremia. (See 'Complications affecting the kidney' above.)

●Hemolysis and neutropenia – Hemolytic anemia can occur when antibodies in the IVIG product react with red blood cell (RBC) antigens (A and/or B; infrequently RhD). Reactions can range from direct antiglobulin (Coombs) test-positivity, mild extravascular hemolysis, and rarely, intravascular hemolysis. Risk factors include high dose, female sex, and non-O blood group. Neutropenia can occur but is generally mild and transient. (See 'Hematologic complications' above.)

●Other reactions – Eczematous dermatitis or reduced efficacy of vaccinations may occur days to weeks following the infusion. IVIG products are extremely unlikely to transmit viruses or prions; however, a theoretical risk exists and information about brand, lot number, expiration date, and manufacturer should be retained for each dose. IVIG can also cause laboratory abnormalities that are generally not considered clinically important. (See 'Late reactions' above and 'Laboratory abnormalities that do not require evaluation' above.)

ACKNOWLEDGMENTS

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

The UpToDate editorial staff also acknowledges extensive contributions of Arthur J Silvergleid, MD, who contributed as an author, to earlier versions of this and many other topic reviews.