Immune Globulins

CMS Pub 100-02 Medicare Benefit Policy Manual, Chapter 15 – Covered Medical and Other Health Services, Section 50.6 – Coverage of Intravenous Immune Globulin for Treatment of Primary Immune Deficiency Diseases in the Home.

CMS Pub 100-03 Medicare National Coverage Determination (NCD) Manual, Chapter 1, Part 4, Section 250.3 – Intravenous Immune Globulin for the Treatment of Autoimmune Mucocutaneous Blistering Diseases.

CMS Pub 100-04 Medicare Claims Processing Manual, Chapter 17 – Drugs and Biologicals, Section 80.6 – Intravenous Immune Globulin (Change Requests 2149, 3745, 4244, 5635, 5643, and 5981).

Immune serums (immune globulin) provide passive immunity to infectious disease. The protection will be of rapid onset, but of short duration (1-3 months). Immune sera are obtained from pooled human plasma of either general population donors or hyperimmunized donors. It may be administered either by intravenous (IV) or intramuscular (IM) injection.

1. Immune globulin is available in broad-spectrum form, or disease-specific hyperimmune serum.
   1. Gamma Globulin; intramuscular IG, Gamma Globulin, ISG, Gamastan, Gammar, is indicated for the following conditions:
      1. Hepatitis A exposure.
      2. Measles (Rubeola): for a susceptible patient (has not been vaccinated or had measles and is at high risk for complication) who has been exposed less than 3 days prior to treatment.
      3. Rubella: for a woman in early pregnancy, who is exposed to the virus and does not have immunity.
      4. Varicella: for passive immunization in immunosuppressed patients when varicella zoster immunoglobulin is not available.
      5. Immunoglobulin deficiency: for prevention of serious infection when circulating IgG levels are low. Prophylactic therapy, especially against infections due to encapsulated bacteria, is often effective in Bruton-type, sex-linked congenital agammaglobulinemia, agammaglobulinemia associated with thymoma, and acquired agammaglobulinemia.
   2. Specific hyperimmune serum globulin includes several different disease-specific drugs.
      1. Hepatitis B serum is indicated post-exposure for transient prevention of hepatitis B infection.
      2. Rabies serum is indicated post-exposure for transient prevention of rabies infection when the patient has not been completely immunized with the vaccination.
      3. Vaccinia serum is indicated for transient prevention of, or modification of aberrant infections induced by vaccinia (smallpox) vaccine, the vaccinia virus, such as eczema vaccinatum, some cases of progressive vaccinia, and possibly ocular vaccinia.
      4. Varicella-zoster serum is indicated for transient prevention of varicella-zoster infection in exposed, susceptible individuals who have a greater risk of complications from varicella. Documentation in the progress notes must indicate one of the following complicating conditions to verify medical necessity:
         - Personal history of leukemia or lymphoma
         - HIV infection
         - Current immunosuppressive therapy
         - A newborn with exposure to chickenpox (the documentation must indicate why the newborn is at increased risk; e.g., if the mother was exposed within 5 days of delivery).
      5. Tetanus serum is indicated for transient protection against tetanus post-exposure to tetanus. Documentation in the progress notes must identify the following:
         - The wound is other than a clean minor wound, and the date of the injury;
         - The active immunization with tetanus toxoid is unknown or uncertain; or
         - The patient has received either less than 2 prior doses of tetanus toxoid; or 2 prior doses of tetanus toxoid, but there has been a delay of 24 hours or more between the time of injury and the initiation of tetanus prophylaxis.
      6. Cytomegalovirus (CMV) immune globulin intravenous (CMV-IGIV) (human) per vial is indicated for the prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, heart, stem cell, and pancreas. In transplants of these organs other than kidney from CMV seropositive donors into seronegative recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir.
      7. Hepatitis B immune globulin (HepaGam B) intramuscular, 0.5 ml is indicated for the treatment of acute exposure to blood containing Hepatitis B Surface Antigen (HBsAg), perinatal exposure of infants born to HBsAg positive mothers, sexual exposure to HBsAg-positive persons, and household exposure to persons with acute HBV infection.
      8. HepaGam B intravenously is indicated for the prevention of Hepatitis B recurrence following a liver transplantation, in HBsAg-positive liver transplant patients.
      9. Crotalidae polyvalent immune FAB (OVINE), (CroFab)
         CroFab is indicated for the management of patients with minimal or moderate envenomation from North American rattlesnakes, copperheads, and cottonmouths/water moccasins. Early use of CroFab (within 6 hours of snakebite) is advised to prevent clinical deterioration and the occurrence of systemic coagulation abnormalities.
2. Intravenous immune globulin (Sandoglobulin, Venoglobulin-I, Privigen, Gamunex, Octagam, Gammagard liquid, Flebogamma/Flebogamma DIF, Carimune, Gammaplex, Bivigam) provides immediate antibody levels. IVIG may be indicated for the following conditions:
   1. Immunodeficiency Syndrome: to include congenital agammaglobulinemia such as x-linked agammaglobulinemia, common variable hypoglobulinemia, x-linked immunodeficiency with hyper IGM, combined immunodeficiency.
   2. Primary thrombocytopenia.
   3. Alloimmune thrombocytopenia, refractoriness to platelet transfusions. Routine use is not indicated. IVIG may have a role in patients with severe thrombocytopenia of documented immune basis for whom other modalities are unsuccessful or contraindicated.
   4. Post-transfusion purpura. IVIG may be considered as first-line therapy in severely affected patients.
   5. Lymphoid Leukemia with either hypogammaglobulinemia or recurrent bacterial infections.
   6. Autoimmune hemolytic anemia (AIHA). Routine use is not indicated. IVIG may have a role in patients with warm-type AIHA that does not respond to corticosteroids.
   7. Immune-mediated neutropenia. Routine use is not indicated. IVIG may have a role in severe illness that does not respond to other modalities or when the latter are contraindicated.
   8. Multiple Myeloma. Routine use is not indicated. It may have a role in patients with stable (plateau phase) disease and high risk of recurrent infections.
   9. Pediatric intractable epilepsy. Routine use is not indicated. IVIG may have a role in certain syndromes as a last resort, especially in patients who may be candidates for surgical resection.
   10. Guillain-Barré syndrome. IVIG is recommended as an equivalent alternative to plasma exchange in children and adults.
   11. Myasthenia gravis (MG). Routine use is not indicated. IVIG may be considered in patients with severe MG to treat acute severe decompensation when other treatments have been unsuccessful or are contraindicated.
   12. Eaton-Lambert Syndrome. This is an immune-mediated, myasthenia-like syndrome. Treatment with IVIG is directed at decreasing the autoimmune response.
   13. Polyneuropathy, chronic inflammatory demyelinating. IVIG is recommended as an equivalent alternative to plasma exchange in adults.
   14. Multifocal motor neuropathy. The routine use of IVIG is not usually recommended. IVIG may be considered in patients who have progressive, symptomatic multifocal motor neuropathy that has been diagnosed on the basis of electrophysiologic findings that rule out other possible conditions that may not respond to this treatment.
   15. Dermatomyositis. Routine use is not indicated. IVIG may be used for patients with severe active illness for whom other interventions have been unsuccessful or intolerable.
   16. Polymyositis. Routine use is not indicated. IVIG may be used for patients with severe active illness for whom other interventions have been unsuccessful or intolerable.
   17. Systemic lupus erythematosus (SLE). Routine use is not indicated. IVIG may be used for patients with severe active SLE for whom other interventions have been unsuccessful or intolerable.
   18. Systemic sclerosis dermatomyositis overlap syndrome. Routine use is not indicated. IVIG may be used for patients with severe active illness for whom other interventions have been unsuccessful or intolerable.
   19. Kawasaki disease.
   20. Severe Vasculitic Syndromes, systemic (polyarteritis nodosa), Churg-Strauss Vasculitis, and livedoid vasculitis (atrophie blanche). Evidence does not support routine use of IVIG. IVIG may be used for patients with severe active illness for whom other interventions have been unsuccessful or intolerable.
   21. Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome. Evidence does not support routine use of IVIG. It will be covered if it is refractory to conventional therapy.
   22. Pemphigoid gestationis that is refractory to conventional therapy.
   23. Pyoderma gangrenosum that is refractory to conventional therapy.
   24. Neonatal alloimmune thrombocytopenia. Routine use of IVIG is not recommended. It is recommended in severely thrombocytopenic, symptomatic neonates who are at high risk of developing intracranial hemorrhage when other interventions have been unsuccessful, become intolerable, or are contra-indicated.
   25. IVIG may be indicated for high-risk pregnant women who have had a history of a previously affected infant with fetal-neonatal thrombocytopenia.
   26. Wiskott-Aldrich Syndrome.
   27. Anemia due to pure red cell aplasia.
   28. Human Immunodeficiency Virus (HIV) infection. IVIG will be covered for patients infected with HIV to reduce significant bacterial infection when all the following coverage indicators are present: a) age less than 13 years old; b) evidence of either qualitative or quantitative humoral immunologic defects and c) current bacterial infections, despite appropriate antimicrobial prophylaxis. Dosage Guidelines: 400 mg/kg body weight given every 28 days.
   29. Autoimmune mucocutaneous blistering disease is covered by a National Coverage Determination (See Pub 100-3: Medicare National Coverage Determination Manual Chapter 1, Part 4 Section 250.3).
   30. Stiff-man syndrome. IVIG may be used for patients with severe active illness for whom other interventions have been unsuccessful or intolerable.
   31. Desensitization for a pre-kidney transplantation in patients with a panel reactive antibody (PRA) of 80% or below. Use in patients with a PRA of 81-100% is considered to be experimental/ investigation and is therefore not covered. Post transplantation to prevent rejection remains covered without regard to antibody levels.
   32. Scleromyxedema, mucinosis of the skin, focal mucinosis, lichen myxedematosus, or reticular erythematous mucinosis.
3. Subcutaneous immune globulin (Hyqvia)
   1. Hyqvia is an immune globulin with a recombinant human hyaluronidase indicated for the treatment of Primary Immunodeficiency (PI) in adults. This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. Hyqvia is administered subQ on an infusion pump which has the ability to titrate the flow rate up or down if required to improve tolerability. WPS GHA Part B will cover the cost as “incident to” for a maximum of 2 episodes to provide teaching in the office setting, effective 12/15/2016. For subsequent doses and titration, coverage shifts to the DME MAC.

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Documentation Requirements
Medical records must include the indications to support using IVIG. For those indications stating routine use is not indicated, the medical record must document the interventions that were unsuccessful or the reason they were not tolerated.

Documentation must support objective response for continued coverage. Medical Records must be made available to the Contractor upon request.

Utilization Guidelines

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Bussel JB. Alloimmune thrombocytopenis in the fetus and newborn. Seminars in Thrombosis and Hemostasis. 2001;(3):245-252.

Callen JP, Jorizzo JL. Skin signs of systemic disease. Best Practice of Medicine. 2000;

CytoGam™ Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV) package insert.

Fischer M, Fiedler E, Marsch WC, Wohlrab J. Antitumor necrosis factor-alpha antibodies (infliximab) in the treatment of a patient with toxic epidermal necrolysis. British Journal of Dermatology. 2002;146(4):707-708.

Gebel HM, Halloran PF. Making sense of desensitization. American Journal of Transplantation. 2010;10:1-2.

Jordan SC, Toyoda M, Jahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. American Journal of Transplantation. 2011;1:196-202.

Kreuter A, et al. Pulsed intravenous immunoglobulin therapy in livedoid vasculitis: an open trial evaluating 9 consecutive patients. Journal of American Academic Dermatology. 2004;51(4).

Montgomery RA. Renal transplantation across HLA and ABO antibody barriers: integrating paired donation into desensitization protocols. American Journal of Transplantation. 2010;10:1-9.

Rongioletti F. Scleromyxedema. UpToDate. Alphen aan den Rijn, The Netherlands: Wolters Kluwer. 2015.

Rutter A, Luger T. High-dose intravenous immunoglubulins: an approach to treat severe immune-mediated and autoimmune diseases of the skin. Journal of the American Academy of Dermatology. 2001;1010-1024.

Silver RM, Porter TF, Branch Esplin MS, Scott JR. Neonatal alloimmune thrombocytopenia: antenatal management. American Journal of Obstetrics and Gynecology. 2000;182(5):1233-1238.