SUMMARY
Immunoglobulin G (IgG) normally represents about 80% of serum immunoglobulin. IgG has a number of important functions in immune defense:
1. Activation of complement
2. Neutralization of toxins
3. Opsonization
4. Antibody-dependent cell cytotoxicity
Opsonization by IgG is particularly important for defense against encapsulated bacteria (H. influenzae, S. pneumoniae, N. meningitidis) - the polysaccharide capsule allows these bacteria to evade ingestion by phagocytes. Immunologic memory following antigenic challenge (through infections or vaccination) is primarily associated with an IgG antibody response.
Transfer of IgG across the placenta peaks during the third trimester of pregnancy and provides a newborn with passive immunity during the first 4-6 months of life. Maternal IgG will gradually diminish and endogenous IgG production will increase.
Patients with primary antibody immunodeficiency and combined (T cell and B cell) immunodeficiency are unable to produce sufficient quantities of immunoglobulins or functional immunoglobulins. Patients with antibody deficiency most commonly develop recurrent sinopulmonary (ear, sinus, lung) infections with encapsulated bacteria at high frequency. However, more invasive infections including sepsis or meningitis may occasionally occur.
Immunoglobulin replacement therapy is a key life-saving intervention for these patients. IVIG preparations primarily contain IgG and only trace amounts of IgA. The IgG is polyclonal and represents the collective antibody repertoire from thousands of plasma donors. This is in contrast to monoclonal preparations such as synagis (recombinant anti-RSV antibody) or Varicella zoster immune globulin.
It is important to adhere to certain standards when treating patients with IVIG. The Eight Guiding Principles of IVIG use in primary immunodeficiency diseases (PIDD) represents consensus practice guidelines published by the AAAAI (see resources).
The Eight Guiding Principles of Ig Therapy in PIDD:
1. Indication - IVIG therapy is indicated as replacement therapy for patients with PIDD characterized by absent or deficient antibody production. This is an FDA-approved indication for IVIG.
2. Diagnosis - There are a large number of PIDD diagnoses for which IVIG is indicated and recommended. Many have low total levels of IgG, but some have a normal level with specific antibody deficiency.
3. Frequency of IVIG Treatment - IVIG is indicated as continuous replacement therapy for primary immunodeficiency. Treatment should not be interrupted once a definitive diagnosis has been established.
4. Dose - IVIG replacement therapy for patients with PIDD is indicated at a starting dose of 400-600 mg/kg every 3-4 weeks. Less frequent treatment, or use of lower doses, is not substantiated by clinical data.
5. IgG Trough Levels - IgG trough levels can be useful in some diagnoses to guide care (ex. hypogammaglobulinemia) but are NOT useful in other diagnoses (ex. specific antibody deficiency). Thus, IgG trough levels should NOT be a consideration in determining access to IVIG therapy.
6. Site of Care - The decision to infuse IVIG in a hospital, hospital outpatient, community office, or home based setting must be based upon the clinical characteristics of the patient.
7. Route - Route of immunoglobulin administration must be based upon patient characteristics. The majority of patients are appropriate for intravenous and a subset for subcutaneous therapy.
8. Product - IVIG is not a generic drug and IVIG products are not interchangeable. A specific IVIG products needs to be matched to patient characteristics to insure patient safety. A change of IVIG product should occur only with the active participation of the prescribing physician.
INDICATIONS
Immunoglobulin replacement is indicated for patients with low IgG quantity or low IgG quality (absent antigen-specific antibody). The classification of antibody immunodeficiencies into four classes has been proposed:
Category B Cells IgG Quantity IgG Quality Diagnostic Examples
I Absent Absent Absent Agammaglobulinemia, SCID
II Present Low Low Hyper IgM, CVID, NEMO
III Present Normal Low Specific Antibody Deficiency, NEMO,
Subclass deficiency with specific antibody defect
IV Present Low Normal Transient hypogammaglobulinemia of infancy
Primary hypogammaglobulinema
TYPES OF REPLACEMENT
Immunoglobulin replacement therapy can be administered as a once a month 4 hour infusion (IVIG) or as a once a week 1 hour subcutaneous infusion (SCIG). The route of delivery should be tailored according to specific needs of the patient. Below is a summary of advantages and disadvantages of IVIG and SCIG.
I. INTRAVENOUS IMMUNOGLOBULIN (IVIG):
Advantages:
Infusion is once a month
Long track record of use
Extensive data regarding dosing regimens and serum IgG levels for patients with PIDD
Disadvantages:
20% of patients experience mild to moderate reactions (migraines, nausea, chills, flushing) which can often be controlled with premedication.
2% of patients experience serious systemic reactions (anaphylaxis, acute renal injury, thrombotic complications).
IV access can be difficult in some patients (ex. infants and younger children).
Must be administered in the hospital/infusion center setting or by a home nurse.
II. SUBCUTANEOUS IMMUNOGLOBULIN (SCIG):
Advantages:
Fewer systemic side effects
No IV access necessary
More consistent serum IgG levels
Some patients may learn to self-infuse the medication, allowing them to gain independence from the hospital or home nurse.
Disadvantages:
More frequent infusions (once a week)
Greater incidence of local site reactions (80-90% initially but falls to below 30% in 1-2 months). Local reactions include swelling, erythema, burning, or itching.
Less data regarding dosing regimens and serum IgG levels for patients with PIDD.
DOSING
A. INTRAVENOUS IMMUNOGLOBULIN (IVIG)
Initial doses of IVIG replacement therapy for a newly diagnosed patient with PIDD are 400-600 mg/kg every 3-4 weeks. Optimal IVIG trough levels (levels obtained at the end of an infusion cycle) achieved should be above 700-800 mg/dl.
The following are typical IVIG infusion rates:
Children < 6yo: 0.5mg/kg/hr increase by 0.5 mg/kg/hr every 15min up to MAX of 3mg/kg/hr
Older Children/Adults: 0.5mg/kg/hr increase by 0.5-1 mg/kg/hr every 15min up to MAX of 4mg/kg/hr
A recent meta-analysis evaluating IVIG administration in PIDD highlighted 2 key points regarding optimization of outcomes with IVIG therapy:
For every 100 mg/kg dose increase in IVIG, a 121 mg/dl trough increased could be expected.
For every 100 mg/dl trough increase, there was a 27% decrease in the incidence of pneumonia.
Thus, if a patient continues to have severe infectious complications following the initiation of IVIG therapy, one approach would be to increase the trough IgG level by administering a higher dose or decreasing the interval between doses (every 3 wks instead of 4 wks for example).
B. SUBCUTANEOUS IMMUNOGLOBULIN (SCIG)
There are a number of subcutaneous immunoglobulin products available in the United States. The following are the initial dosing guidelines for 3 products:
-Gammunex-C (10%): 1.37 times the IV dose is divided by 4 infused once a week.
-Hizentra (20%): 1.53 times the IV dose is divided by 4 infused once a week.
-Gammagard Liquid (10%): 1.37 times the IV dose is divided by 4 infused once a week.
Up to 15ml of SCIG is infused per infusion site (typically in the abdomen, thighs, or upper buttocks). Typically more than one site is required to infuse the appropriate volume. The 15ml of SCIG per site is infused over 1 hour (no gradual increase in rate is required). Data from efficacy trials for SCIG indicate that trough IgG levels should be maintained above 900 - 1000 mg/dL.
ADVERSE REACTIONS
Adverse reactions to IVIG occur in approximately 20 percent of recipients. Most reactions are mild, transient, and manageable with pre-medication or rate adjustments. However, rare but serious reactions are also possible. Adverse reactions occur more commonly when a patient is receiving immunoglobulin replacement for the first time or changing from one product to another (for this reason, the first infusion of a new product should occur under medical supervision in the hospital or infusion unit).
I. MILD REACTIONS: Most IVIG reactions fall into this category and include the following symptoms:
• Headache
• Chills
• Malaise
• Dyspnea
• Urticaria
Patients experiencing these types of reactions typically respond well to temporary discontinuation of the infusion. Pre-treatment with NSAIDs (ibuprofen), antihistamines, or glucocorticoids prior to the infusion as well as running the infusion at a slower rate may decrease the symptoms.
Headache is a common side effect and may appear as late as 24 to 48 hours after the infusion and may last for one to three days. In some patients, the severity of headaches may decrease after a number of infusions.
Pretreatment with ibuprofen or glucocorticoids and infusion of IVIG at a slower rate may help to prevent headaches. In some cases, NSAIDs and steroids may need to be continued for 24-72 hours following the completion of the infusion. Adequate hydration is also important in order to prevent headaches. Pre-infusion oral hydration, IV fluid bolus prior to the infusion, or concurrent IV fluid administration during the infusion may help to decrease headaches.
II. SERIOUS REACTIONS: Serious reactions are rare reported in approximately 2% of patients receiving IVIG.
• Acute Renal Injury and Failure - This serious complication occurs in less than 1% of patients receiving IVIG. Symptoms range from elevated creatinine to anuric renal failure. Spontaneous resolution occurs for most patients (4-10 days following cessation of IVIG) but permanent damage has also been reported. This adverse event is typically caused by sucrose-containing IVIG products (the sucrose is taken up by renal tubular cells and the increased solute load causes the cells to swell and obstruct the tubules). Thus, sucrose-containing IVIG products should be avoided in patients with pre-existing renal disease. The deposition of newly formed immune complexes in the kidneys is another mechanism by which acute injury may occur.
• Thrombotic complications - IVIG can transiently increase blood viscosity. Local thrombosis at the site of infusion as well as stroke and myocardial infarction may occur. Risk factors include older age, dehydration, hypercoagulable states, or patients receiving high doses of IVIG. Due to the risk of this complication, the use of implantable catheters in patients receiving IVIG should be approached with caution (implantable catheters themselves carry the risk of thrombus formation).
• Anaphylaxis - Patients with undetectable IgA levels are at increased risk for anaphylactic reactions when receiving IVIG products containing IgA. This occurs due to preformed IgE or IgG antibodies directed against IgA. This reaction is a potential concern for patients with partial humoral immunodeficiency who are able to produce some immunoglobulins (ex. CVID). It is not considered a threat for patients unable to make any immunoglobulins (ex. XLA). IVIG products with the lowest amounts of IgA should be considered for such patients. Anaphylactic reactions should be treated with IM epinephrine and H1/H2 blockade.
• Severe fevers, rigors, flu-like symptoms - Patients with acute infections who receive IVIG may experience chills, fever, myalgias, and arthralgias. These symptoms likely result from the lysis bacteria resulting from rapid release of bacterial antigens followed by activation of complement due to immune complex formation. The rapid release of LPS and other microbial proteins may also trigger TLR-signaling pathways leading to the release of pro-inflammatory cytokines. Active infections should be treated with antibiotics prior to IVIG administration when possible
DISEASE LINKS
The following are specific examples of primary immunodeficiencies for which immunoglobulin replacement therapy has been routinely utilized (this is not a comprehensive list):
X-Linked Agammaglobulinemia - Patients with XL and AR agammaglobulinemia lack B cells and are unable to produce immunoglobulins. Patients have low IgG, IgM, IgA, and lack specific responses to vaccine antigens.
CVID - Patients with CVID typically have B cells but they have low serum IgG levels and poor specific antibody production.
Specific Antibody Deficiency (SAD) - Patients with SAD have normal B cell numbers and normal total IgG levels but have poor responses to specific vaccine antigens (most commonly pneumococcus).
X-Linked Hyper IgM Syndrome (CD40L deficiency) - Patients have normal B cell numbers but low IgG levels and poor specific responses to vaccine antigens due to an inability to class switch from IgM to other immunoglobulin isotypes (IgG, IgA, IgE)
Autosomal Recessive Hyper IgM Syndrome (AID, UNG, CD40) - Patients have normal B cell numbers but low IgG levels and poor specific responses to vaccine antigens due to an inability to class switch from IgM to other immunoglobulin isotypes (IgG, IgA, IgE).
Wiskott-Aldrich Syndrome - Patients typically have normal B cell and IgG levels. However, diminished antibody responses to polysaccharide antigens is present (ex. pneumococcus)
NEMO Deficiency - A subset of patients have normal B cell numbers and normal total IgG levels but have poor responses to specific vaccine antigens due to impaired isotype class switching.
Severe Combined Immunodeficiency (SCID) - There are more than 30 different types of SCID that have been reported to date. A common feature of most types of SCID is the absence of T cells. Although B cells are present in many types of SCID (X-linked SCID, JAK3 deficiency, IL-7R deficiency, CD3 deficiency, etc.), antibody production is absent without CD4 T cell co-stimulatory signaling. All patients with SCID should receive IVIG replacement therapy and Pneumocytis jiroveci prophylaxis. However, this represents only a temporary measure to reduce infection survival is poor without HSCT. Even following successful HSCT, many patients fail to have B cell engraftment and may require lifelong IVIG replacement therapy.
RESOURCES
Literature Resources
1. AAAAI
8 guiding principles of IVIG use
2. Perez 2017
Update on the use of immunoglobulin in human disease: A review of evidence
2. Stiem 2010
Therapeutic use of Immunoglobulins
3. Orange 2010
Impact of trough IgG on pneumonia incidence in PID - meta-analysis
4. Orange 2006
Use of IVIG in human disease - a review of evidence by PID committee of AAAAI
CASE STUDIES