Each issue of the CoramClick provides an in-depth focus on timely and practical solutions. In this issue of the Click, we are focusing on IVIg. Back issues of th Click are available in the CoramClick archive for easy reference!

	What is IVIg Used For? Intravenous immunoglobulin (IVIg) has two primary functions: 1) to provide passive immunity in patients unable to produce any or enough of their own antibodies; and 2) as an immune system modulator.	IVIg in Organ Transplant As in many clinical areas, the use of IVIg in solid organ transplant continues to expand in both indications and numbers of prescribers. IVIg has also been found to down-regulate the immune system in pre-transplant patients who are “highly sensitized”, allowing more patients to receive transplants and improve long-term outcomes. Subscribe to the CoramClick Please include your email address, first and last name, and company name.
	Subcutaneous Immunoglobulin: A Self-infusion Alternative to IVIg As a self-infusible alternative to IVIg, subcutaneous administration minimizes patient time away from school, work, family activities, etc. and decreases the risk of infection.

What is IVIg Used For?

Intravenous immunoglobulin (IVIg) has two primary functions: 1) to provide passive immunity in patients unable to produce any or enough of their own antibodies; and 2) as an immune system modulator.

Passive Immunity

The body’s normal immune response includes the production of antibodies, or immunoglobulins, against foreign pathogens. The primary circulating immunoglobulin is IgG, making up approximately 70–75 percent of the body’s immunoglobulin content. IgG’s major function is to neutralize viruses and toxins and to bind to and opsonize bacteria.

For patients who have diminished or no capability to produce antibodies, infection poses a significant and potentially fatal threat. IVIg has been referred to as “antibodies in a bottle” since it provides antibodies the patient may not have, thus supporting the fight against infection.

IVIg is pooled from between two and ten thousand plasma donors. The plasma is screened for virus, and then fractionated, enhanced to create a solution of about 95 percent IgG, and then is purified. The solution is infused, typically every three to four weeks, to help patients maintain an effective IgG serum level.

Immunomodulation

Immunoglobulins also work to suppress inflammation, although the exact mechanism of this effect is unclear. For this reason, IVIg is often used to treat several autoimmune disorders of the nervous system. Autoimmune diseases occur when inflammatory reactions take place against the body’s own cells and tissues. IVIg is intended to decrease the severity of the inflammatory response and thus decrease the severity of the disease.

IVIg’s immunomodulating capabilities also support its use in blood cell transplantation to decrease the development of acute graft-versus-host disease (GVHD).

The Food and Drug Administration (FDA) has approved the use of IVIg in seven disease states or categories, as can be seen in the list to the right. However, the use of IVIg continues to expand in both indications and numbers of prescribers as benefit is realized in more and more clinical situations.

Disease-specific Uses

Some IVIg products have been prepared to treat specific disease states. For example, hepatitis B immunoglobulin (HBIg) is often used to prevent the development of hepatitis b after exposure, as well as to reduce the incidence of recurrent hepatitis B in a transplant patient with the disease. IVIg with a large concentration of antibodies to cytomegalovirus (CMV) is often indicated to prevent CMV infection in transplant patients, particularly if the organ recipient has not been exposed and therefore does not have antibodies to CMV.

Subcutaneous Immunoglobulin:
A Self-infusion Alternative to IVIg

Intravenous immunoglobulin (IVIg) has proven an effective therapeutic option for many disease states and has long been the standard of care for patients requiring antibody replacement, patients with autoimmune disease, and many others. Intravenous infusion is the primary route of administration. However, subcutaneous immunoglobulin (SCIg) was approved by the Food and Drug Administration (FDA) in 2006 for Vivaglobin^® (CSL Behring) as an alternative to intravenous administration.

Patients who administer subcutaneously can be serviced in the home setting, a particular advantage for small children who frequently require hospitalization for their doses. As a self-infusible alternative to IVIg, subcutaneous administration minimizes patient time away from school, work, family activities, etc. and decreases the risk of infection. Subcutaneous Ig may be appropriate, for example, for patients who have poor venous access, have intolerable side effects to IVIg, are at risk for volume overload or congestive heart failure, have busy lifestyles, or who are not able to achieve satisfactory Ig levels from the IV route. There are, however, important disadvantages as well. Weekly infusions are typically required, and in some cases, with higher doses or patient preference (related to administration time or volume), dosing may be prescribed for more than once a week.

Numerous factors must be considered when determining the most appropriate route of administration, not the least of which is patient preference. Important differences to consider include:

SCIg Administration

Dosing for weekly administration is typically the patient’s monthly total dose of IVIg, multiplied by 1.37 percent, and then divided into equal doses based on the frequency of their monthly dosing. For example, a patient who administered IVIg q four weeks would multiply their monthly dose by 1.37, then divide by 4 to arrive at their weekly SCIg dose. Assessment for pre-medication requirements is the same as for intravenous administration. Many patients, however, require no pre-medication. IVIg patients who are switching to the subcutaneous route are considered to be a brand change or first dose patient and require monitoring and anaphylaxis precautions. Ig naïve patients may require an IV dose first or may begin SCIg with daily dosing for five days before changing to weekly dosing. Some patients may require lower initial SCIg dosing and titrate to a full dose over a few weeks.

Depending on the dose (i.e. volume), multiple sites may be needed for each infusion. All subcutaneous sites are acceptable, although the abdomen and thigh are preferred. Site rotation is based on a maximum of 15-20 ml/site, but some patients are able to handle higher volumes. Some patients may prefer topical anesthetics or ice prior to needle insertion, at least in the beginning.

Therapeutic effectiveness is measured by IgG serum concentration, with a goal of at least 500 mg/dL. Peak Ig levels typically occur four days post-infusion, but the time to reach desired levels varies.

SCIg has proven equally effective and demonstrates safety, a low adverse effect profile, and a positive impact on quality of life, treatment satisfaction, independence, and total costs.

Note: At the time of this writing, Vivaglobin is the only immunoglobulin product FDA-approved for subcutaneous administration. Other products are anticipated to receive similar approval in 2010.

IVIg in Organ Transplant

As in many clinical areas, the use of IVIg in solid organ transplant continues to expand in both indications and numbers of prescribers. For example, long-term Hepatitis B immunoglobulin (HBIg) is often used, typically in combination with the antiviral agent lamivudine, to reduce the viral load in a pre-transplant patient infected with the hepatitis B virus and then long-term post-transplant to sustain viral inhibition. IVIg with a large concentration of antibodies to cytomegalovirus (CMV) is often indicated to prevent and/or treat the common CMV infection post transplant, particularly if the organ recipient has not been exposed and therefore does not have antibodies to CMV.

IVIg has also been found to down-regulate the immune system in pre-transplant patients who are “highly sensitized”, allowing more patients to be transplanted and improve long-term outcomes. Approximately 30 percent of patients awaiting transplant are sensitized. They have antibodies against a large percent of human tissue antigens and thus will react against many donors. A “positive cross-match” disallows transplant with that particular donor. Patients with a high percent reactive antibody (PRA) have a severely limited chance to find a donor with whom they will not react. Many patients wait years for a transplant, and a significant percent will not be able to be transplanted at all.

IVIg administered in the pre-transplant phase significantly decreases PRA levels and improves a sensitized patient’s chances to be able to accept a donor organ. IVIg has also been shown to improve both short- and long-term transplant success. Desensitization protocols typically include monthly high-dose IVIg administration for four to six months until their PRA reaches an acceptable lower level. Since antibody levels will rebound, booster doses at 12 and 24 months is required if the patient has not yet been transplanted. An additional dose is given at one month post-transplant. For patients who are awaiting a cadaver donor, an additional dose is given at the time of transplant (as a component of the “induction” therapy”).

Protocols might include IVIg as single therapy, but may also include other means of immunomodulation including plasmapheresis, rituximab, and/or other immunosuppressant medication(s).

IVIg administration pre-transplant has shown a decreased incidence of rejection and may also help reverse a rejection episode. Approximately 20-30 percent of patients who receive IVIg as part of their pre-transplant desensitization protocol will still experience an acute antibody-mediated rejection (AMR), an aggressive rejection response which requires aggressive intervention. Approximately 10 plasmapheresis treatments, followed by IVIg infusion, may be used in attempt to reverse the rejection.

Patients who experience AMR are also a greater risk for post-transplant glomerulonephritis. IVIg is currently under study for this purpose.

Benefits of IVIg in Organ Transplant

The prevention of post-transplant hepatitis with HBig and prevention or treatment of CMV are critical for long-term transplant success in appropriate patients.

The ability to perform a transplant in a patient who is otherwise unlikely to receive one is significant — both clinically and economically. Given that transplant is the last treatment option for many, death is likely in the patient unable to receive a transplant. In kidney transplantation, a patient would necessarily stay on dialysis for many years while waiting for a kidney. Early transplantation results in costs savings, reduced morbidity and mortality, and improved quality of life.

Benefits to a transplant program include the opportunity to provide state-of-the-art therapy and to increase the number of patients able to be transplanted. Both enhance center reputation and revenues. Payors benefit similarly, providing an opportunity for cost savings for patients awaiting transplantation as well as the prevention/treatment of transplant rejection.

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