Indications

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Note
  • For infants with XLA, consider starting IVIG when specific antibody levels (e.g. hib) fall below protective range (typically around 3 months of age) even if total IgG level is still within normal range


Polyclonal Immunoglobulin Products

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Special Precautions for IVIG Brands

  • Sucrose (Caramune): avoid in renal risks due to association with acute tubular osmotic nephrosis
  • Glucose (Gammagard SD): avoid in diabetes
  • Maltose (Octagam): false readings with glucose monitor
  • Sodium (Gammagard SD ‐ 0.85%, Caramune): avoid in infants and cardiovascular risks
  • High Osmolarity (Gammagard SD): avoid in infants and cardiovascular risks
  • Fluid load (5% preparations – Flebogamma, Octagam): avoid in water restriction, caution in infants.
  • Amino acids (Glycine in Gammunex/Gammagard Liq, Proline in Privigen): avoid in specific reactivity or certain metabolic disorders
  • IgA (all except Gammagard SD) – avoid in patients with IgA deficiency, history of reaction
  • Lyophilized products (Carimune, Gammagard SD): associated with thromboembolic events in patients with autoimmune disease

Characteristics may be less relevant with subcutaneous therapy




IVIG Dosing

  • The goal of immunoglobulin replacement in patients with primary antibody deficiencies should be to reduce breakthrough infections rather than to achieve a particular IgG trough level.
    • Starting doses: 400 to 600 mg/kg/month for a target trough level of at least 500 mg/dL
      • Starting dose of 400 mg/kg/month used for patients without chronic lung disease; 600 mg/kg/month for those with bronchiectasis.
      • In patients starting with higher IgG levels, a rough goal is serum trough level equal to pretreatment level plus 300 mg/dL
      • Doses are adjusted in line with breakthrough infections (biological trough level). A rate of 3 moderate bacterial infections per year justifies an increase in immunoglobulin dosage of around 150 mg/kg/month.
        • Every 100 mg/kg trough level increase decreases pneumonia incidence by 27% (no threshold identified up to 1000 mg/dl trough, where data end)
        • When changing the dose, it may take 3 infusions to equilibrate to a new trough
        • Interval may also be adjusted (q4 to q2-3 weeks)
    • Trough IgG generally increases 121 mg/dL for every 100mg/kg dose increase.
  • Special cases
    • Bronchiectasis - due to increased catabolism and/or loss, these patients require twice as much replacement therapy to achieve the same IgG level compared to those without.
    • Pregnancy - higher doses are necessary in the third trimester due to volume expansion. Increasing the dose assures transfer of adequate IgG across placenta to fetus.




Adverse Reactions to IVIG


Common Adverse Reactions

  • Usually related to infusion rate
  • Occur in 5-10%, usually during infusion but can occur 6-24 hours later
  • Occur most commonly during first time infusion in newly diagnosed hypogammaglobulinemia patients with active infection
  • Mechanisms of adverse reaction include activation of complement by Ig complexes in IVIG, vasoactive proteins in IVIG (contaminants), lysis of bacteria in patients with a heavy bacterial load (active infection, first time infusion of IVIG), patient with IgA deficiency (see above)
  • Most symptoms are mild and reversible
    • Fever, chills, facial flushing
    • Tachycardia, palpitations
    • Dyspnea, chest tightness or pain
    • Nausea, abdominal pain
    • Back pain, arthralgia, myalgia
    • Hypotension, shock
    • Aseptic meningitis - frequent with high dose IVIG, history of migraine is a risk factor
    • Hemolysis - treat with type O packed red cells


General Management

  • Slow or temporarily stop infusion
  • Consider pretreatment with acetaminophen, NSAIDs, antihistamines (steroids rarely needed)
  • Restart at previous rate at which there were no adverse reactions
  • Consider changing to subutaneous administration which has less systemic side effects

IVIG in Patients with IgA Deficiency (<7 mg/dL)

  • Anti-IgA antibodies have been reported to increase risk of adverse reactions (including anaphylaxis) to IVIG products that may contain some IgA (see IVIG products table above), but the predictive value of this test is unclear (especially if not very elevated)
  • Up to 40% of patients with selective IgA deficiency and 9-25% of patients with CVID may have anti-IgA IgG.
    • Anti-IgA IgE has been found much less frequently but may further increase risk of anaphylaxis due to presumed type-I IgE mediated hypersensitivity
    • Anti-IgA antibodies may be class specific and bind both IgA1 and IgA2; subclass specific anti-IgA binds only 1 subclass (IgA1, IgA2m[1], or IgA2m[2]). It is not clear that presence of class-specific vs. subclass-specific IgG anti-IgA antibodies have clinical relevance.
  • Patients with anti-IgA IgG antibodies and adverse reactions to IVIG are reported to tolerate SCIG
  • Patients with anti-IgA IgG antibodies may tolerate IVIG products with low IgA levels (ie, Gammagard SD)
    • If a patient who is IgA deficient is reacting to IVIG and SCIG is not an option (eg, a high dose of IVIG is needed), then consider using a low-IgA content product, especially if there is a high level of IgG anti-IgA antibodies present
  • Alpha-1 antitrypsin replacement therapy (e.g. Prolastin) may contain IgA
  • IgA‐deficient subjects should receive washed red blood cells and no whole blood to avoid exposure to exogenous IgA


Subcutaneous IVIG (SCIG)

  • Advantages include: no IV access needed, no trough levels needed, less systemic side effects, can be done at home
  • Disadvantages: frequent dosing because of limitation of volume able to be infused into a single SC site, local reactions, patient adherence, home infusion pump needed


SCIG Dosing


How to dose SCIG (Vivaglobin)
  • For subcutaneous infusion only. DO NOT INJECT INTO A BLOOD VESSEL.
  • Start patients on treatment with Vivaglobin 1 week after having received Immune Globulin Intravenous (Human) (IVIG) infusions at regular intervals for a period of at least 3 months.

  • Initial Weekly Dose
    • The initial weekly dose of Vivaglobin is calculated to achieve a systemic serum IgG exposure (area under the concentration-time curve [AUC]) not inferior to the AUC of the previous IVIG treatment.
    • Vivaglobin weekly dose (in grams [g]) = [1.37 x previous IVIG dose (g] / Number of weeks between IVIG doses
    • Divide by 0.16 to convert the dose in g to milliliters (mL).

  • Dose Adjustment
    • Doses may need to be adjusted over time based on the patient’s clinical response and serum immunoglobulin G (IgG) trough levels.
    • To determine if a dose adjustment should be considered, measure the serum IgG trough level during IVIG therapy prior to switching to Vivaglobin and again after 2 to 3 months of treatment with Vivaglobin. Adjust the Vivaglobin dose to achieve a serum IgG trough level that is equal to the last trough level during prior IVIG therapy plus 180 mg/dL.

  • Administration
    • Infuse subcutaneously, preferably in the abdomen, thigh, upper arm, and/or lateral hip.
    • Divide doses >15 mL and infuse into multiple sites that are at least two inches apart.
      • Adults – Up to six simultaneous sites
      • Children <45 kg (99 pounds) – Up to three simultaneous sites
      • Patients ≥65 years – Up to four simultaneous sites
      • If necessary, additional sites can be used consecutively during an infusion.
    • Administer at a rate of ≤20 mL/hour per site. The maximum infusion rate should not exceed a total of 3 mg/kg/minute (1.13 mL/kg/hour) for all simultaneous infusion sites combined.
    • Ensure that patients are not volume depleted.


Infusion Pumps





References