Immune globulin or immunoglobulin (Ig) is a blood product that is given for the treatment of primary immunodeficiency diseases featuring low or dysfunctional antibody levels and of certain inflammatory, autoimmune and other diseases featuring low antibody levels. Ig is also used for removal of harmful antibodies and for blocking damage from immune cells.

This document does not pertain to the use of:

• Rho (D) Immune Globulin and WinRho SD injections for the prevention or treatment of Rh incompatibility; or
• Specific hyperimmune serum globulin after exposure to Botulinum, Cytomegalovirus, Diphtheria, Hepatitis B, Rabies, Tetanus, Vaccinia, or Varicella-Zoster; or
• Any Ig product for prophylaxis against disease (e.g., GamaSTAN^® for hepatitis A prophylaxis).

 Note: Please see the following related documents for additional information:

• DRUG.00013 Intravenous Immunoglobulin as a Treatment of Recurrent Spontaneous Abortion 
• CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use 

Medically Necessary: 

Immune globulin (Ig) therapy is considered medically necessary for the U.S. Food and Drug Administration (FDA) approved indication:

• Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) for an initial trial (up to 12 weeks), when the medical record indicates that the clinical presentation is not consistent with other polyneuropathies (e.g. IgM neuropathy, hereditary neuropathy, diabetic neuropathy) and ONE of the following clinical and electrodiagnostic criteria are met:
  • There is proximal muscle weakness or sensory dysfunction caused by neuropathy and nerve conduction studies (NCS) confirm there is electrodiagnostic evidence of a demyelinating neuropathy in at least two limbs; or
  • There is distal muscle weakness and results of diagnostic testing meet a recognized set of diagnostic criteria as established by the American Academy of Neurology (AAN), Saperstein, or Inflammatory Neuropathy Cause and Treatment (INTAC).
• Continued use of Ig after initial trial for CIDP is medically necessary when the following criteria are met:
  • Clinically significant improvement in neurological symptoms is documented on physical examination; and
  • Continued need is demonstrated by documentation that attempts on an annual basis to titrate the dose or the interval of therapy result in worsening of symptoms.

The following FDA approved indications are also considered medically necessary for immune globulin (Ig) therapy:

• Treatment of primary humoral immunodeficiency (e.g. congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked immunodeficiency, severe combined immunodeficiency (SCID), or Wiskott-Aldrich syndrome) when:
  • There is no evidence of renal (nephrotic syndrome) and gastrointestinal (e.g. protein losing enteropathy) as causes of hypogammaglobulinemia; and 
  • Total IgG is less than 500 mg/dl.
• Treatment of IgG sub-class deficiency (IgG1, IgG2, IgG3, IgG4) when:
  • One or more serum IgG subclasses are more than two standard deviations below the lower limits of the age adjusted norm; and
  • History of recurrent  sinopulmonary infections requiring antibiotic therapy; and
  • Lack of, or inadequate response to immunization (for example, but not limited to pneumococcal antigen).
• Treatment of Kawasaki Syndrome:
  • Within 10 days of onset; and
  • Treatment for no more than 5 days.
• Treatment of immune thrombocytopenia [(idiopathic thrombocytopenic purpura (ITP)] in individuals with either of the following;
  • Symptomatic thrombocytopenia (for example, but not limited to hematuria, petechiae, bruising, gastrointestinal bleeding, gingival bleeding); or
  • Platelet count less than 20,000 (adult) or 30,000 (child).
• Treatment of individuals with hypogammaglobulinemia and recurrent bacterial infection associated with B-cell chronic lymphocytic leukemia (CLL) that includes both:
  • Documented history of recurrent bacterial infection or an active infection not responding to antimicrobial therapy; and
  • Documentation that total IgG is less than 500 mg/dl.

Immune globulin (Ig) therapy is considered medically necessary for the following off-label indication:

• Multifocal Motor Neuropathy (MMN) initial trial (up to 4 weeks), when ONE of the following criteria are met:
  • There is asymmetric weakness that predominantly affects distal muscles (without upper motor neuron signs) AND nerve conduction studies confirm a demyelinating neuropathy is present (conduction block, slowing, or abnormal temporal dispersion in at least one nerve); or
  • Clinical history and exam do not suggest upper motor neuron disease (no bulbar weakness, no upper motor neuron signs) and labs show that GM-1 antibody titers are elevated; or
  • After the initial exam and electrodiagnostic testing clinical presentation suggests MMN but the diagnosis remains uncertain.

• Continued use of Ig after initial trial for MMN when the following criteria are met:
  • Clinical results document an improvement in strength and function within three weeks of the start of the infusion period;
  • Continued need is demonstrated by documentation that attempts on an annual basis to titrate the dose or the interval of therapy result in worsening of symptoms.

Immune globulin (Ig) therapy is also considered medically necessary for the following off-label indications:

• Antenatal alloimmune thrombocytopenia;
• Autoimmune neutropenia;
• Dermatomyositis, refractory; (IVIG is used as a second line treatment of dermatomyositis.  Corticosteroids are first-line treatments of dermatomyositis); 
• Eaton-Lambert myasthenic syndrome treatment;
• Guillain-Barre Syndrome (acute demyelinating polyneuropathy) as an equivalent alternative to plasma exchange;
• Hyperimmunoglobulinemia E syndrome (HIE) treatment;
• Myasthenia Gravis, severe refractory;
• Polymyositis; routine use of Ig is not recommended. Ig may be considered in individuals with severe polymyositis for whom other treatments have been unsuccessful, have become intolerable, or are contraindicated;
• Prior to a medically necessary solid organ transplantation for suppression of panel reactive anti-HLA antibodies in individuals with high panel reactive antibody (PRA) levels to human leukocyte antigens (HLA);
• Prevention of infections in high-risk, preterm, low birth weight neonates;
• Stiff-person syndrome not controlled by other therapies;
• Toxic shock syndrome caused by staphylococcal or streptococcal organisms refractory to several hours of aggressive therapy;
• Solid organ transplant recipients at risk for CMV;
• Treatment of chronic parvovirus B19 infection and severe anemia associated with bone marrow suppression;
• To reduce the risk of graft-versus-host disease associated with interstitial pneumonia (infectious or idiopathic) and infections (cytomegalovirus infections, varicella-zoster virus infection, and recurrent bacterial infection) in allogeneic bone marrow transplant (BMT) recipients in the first 100 days after transplantation;
• Prevention of infection in HIV infected children;
• Refractory auto-immune mucocutaneous blistering diseases including:  pemphigus vulgaris, pemphigus foliaceous, bullous pemphigoid, mucous membrane pemphigoid, and epidermolysis bullosa aquisita;
• Secondary hypoglobulinemia in individuals who are immunosuppressed (for example status-post bone marrow transplant) and have a documented total IgG less than 500 mg/dl.

 Not Medically Necessary:

• Immune globulin (Ig) therapy is considered not medically necessary for the indications listed above when criteria are not met.
  
• Immune globulin (Ig) therapy is considered not medically necessary for all other indications not listed above as medically necessary, including but not limited to:
  • Multiple sclerosis;
  • Immune optic neuropathy.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

Our bodies naturally produce antibodies to fight and create immunity against disease-causing agents such as viruses and bacteria when infections occur. Once the body has been exposed to an infection, antibodies can sometimes protect us from becoming ill if we are exposed to the same infectious agents sometime in the future.  Under many circumstances a person's ability to produce their own Immune globulin (Ig) is impaired and the use of other methods to boost the immune system becomes necessary. Ig is a sterilized solution obtained from pooled human blood plasma, which contains the immunoglobulins (or antibodies) to prevent various infectious diseases. Ig is sometimes used to aid in the prevention or progression of an illness by using a donor's antibodies to fight the illness. This process is referred to as passive immunity, as opposed to active immunity in which the individuals's body is making its own antibodies. Passive immunity conveys only temporary protection and should not be confused with getting an immunization, which provides longer-term protection. The duration of Ig treatment is extremely variable depending upon the condition being treated and the individual receiving the therapy.

For some conditions retreatment may not be needed, however some individuals may require treatment every 3-4 weeks and others every 6-8 weeks.

Pooled Ig preparations contain many different types of immune globulins (differentiated on the basis of structure and biological activity) that target different specific immune functions of the body. In this way, Ig imparts several types of immune fighting antibodies simultaneously. The anti-inflammatory mechanisms of Ig action remains undetermined. The therapeutic mechanism and the short-and long-term effects may not be the same for each condition.

There are five types or classes of immunoglobulin: IgG, IgA, IgM, IgD and IgE. The most prevalent immunoglobulin present in the body is IgG. The IgG class of antibodies is itself composed of four different subtypes of IgG molecules called the IgG subclasses. These are designated IgG1, IgG2, IgG3 and IgG4. Individuals who suffer recurrent infections because they lack, or have very low levels of, one or two IgG subclasses, but whose other immunoglobulin levels, including total IgG, are normal, are said to have a selective IgG subclass deficiency.

Since preparations of Ig are derived from donor blood, concerns about the potential for contracting diseases, such as hepatitis and HIV exist, the process used to prepare Ig for use in humans is monitored by the manufacturer and the FDA for the presence of infectious agents.  The monitoring process begins with the screening of potential donors. Next, all manufacturers use a multi-step process that extracts the desired immune globulins and attempts to remove all other substances. Finally, samples of each batch of Ig are tested for the presence of infectious particles.  While all attempts are taken to reduce the risk of infection in the use of Ig, some small risk still exists.  Potential recipients of this treatment should take this risk into consideration when contemplating Ig therapy. 

Immune globulin can be given subcutaneously (SC), intramuscular (IM) or intravenously (IV). Some examples of immune globulin products and the route of administration are:

• Immune Globulin intravenous (IV): Carimune^®_,  Flebogamma^®_,  Gammagard^®_, Gammaplex^®_,  Gamunex^®_,  Octagam^®_,  Panglobulin^®_, Privigen^®_, Polygam^®_;
• Immune Globulin intramuscular (IM): GamaSTAN^®_;
• Immune Globulin Subcutaneous (SC): Vivaglobin^®_, Hizentra^®_,Gamunex-C^®_,        

The development of this document is based on the FDA labeling, practice guidelines of medical specialty organizations, published literature and drug compendia off label indications. 

The American Academy of Neurology (AAN) in their 2002 guideline, Disease modifying therapies in multiple sclerosis, addresses intravenous immune globulin (IVIg) for the treatment of multiple sclerosis and states:

The studies of intravenous immunoglobulin (IVIg), to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes or have used methods that have been questioned. It is, therefore, only possible that IVIg reduces the attack rate in RRMS (Type C recommendation*). The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression (Type C recommendation*).
*Type C recommendation C—Possibly effective, ineffective or harmful for the given condition in the specified population.

The American Academy of Allergy Asthma and Immunology (AAAAI), in their Work Group Report on the appropriate use of intravenously administered immunoglobulin (2005) states:

IVIG may also be a potentially effective second line treatment in relapsing-remitting multiple sclerosis, although the optimal dosage remains to be established.*

*AAAAI Position Statements and Work Group Reports are not to be considered to reflect current AAAAI standards or policy after five years from the date of publication. For reference only. January 2005

The American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) jointly published the Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency where IgG subclass deficiency diagnostic criteria were addressed:

In individuals with recurrent infections and 1 or more low levels of IgG subclasses, a demonstrable impairment in antibody response to vaccination or natural exposure is considered the most important determinant of disease  (Bonilla, 2005).

The American Academy of Otolaryngology–Head and Neck Surgery Foundation guideline, Clinical practice guideline: Adult sinusitis (2007) concluded that treatment with intravenous immune globulin (IVIg) for chronic sinusitis or recurrent acute rhinosinusitis in those with humoral immune deficiency requires more research.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a neurological disorder characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder, which is sometimes called chronic relapsing polyneuropathy, is caused by damage to the myelin sheath (the fatty covering that wraps around and protects nerve fibers) of the peripheral nerves. This myelin damage is often documented by nerve conduction study or nerve biopsy and there is often evidence of elevated CSF protein during the course of the disease. CIDP is difficult to diagnose due to its heterogeneous presentation (both clinical and electrophysiological). Sander and Latov (2003) acknowledged the diagnostic difficulty of CIDP. They attributed this in part to the lack of clarity with the diagnostic criteria for CIDP. Without proper diagnostic criteria, many individuals might remain untreated. In their publication, Sander and Latov (2003) presented the American Academy of Neurology (AAN), Saperstein Diagnostic Criteria and the Inflammatory Neuropathy Cause and Treatment (INCAT) electrodiagnostic criteria.

Although CIDP can occur in both genders at any age, it is more common in young adults and in men more so than women. CIDP is closely related to Guillain-Barre syndrome and it is considered the chronic counterpart of that acute disease. The Food and Drug Administration (FDA) approved Gamunex^® for the treatment of CIDP in September 2008. The FDA based its approval on clinical trials that showed Gamunex^® was effective at improving certain motor functions for up to 48 weeks after the initial treatment.

Ig has been studied for treatment of autoimmune optic neuropathy, specifically, optic neuritis (ON). Roed and colleagues (2005) conducted a randomized controlled trial of 68 participants receiving IVIg (n=34) and a control group (n=34) to investigate whether IVIg treatment in the acute phase of ON could improve visual outcome and reduce disease activity as measured by MRI 6 months after disease onset. Infusions were given at days 0, 1, 2, 30, and 60. Contrast sensitivity, visual acuity, and color vision were measured at baseline and after 1 week, 1 month, and 6 months. Pattern reversal visual evoked potential studies and gadolinium-enhanced MRI were performed at baseline and after 1 and 6 months. There was no difference in the primary outcome, contrast sensitivity after 6 months, between participants randomized to treatment with IVIg or placebo. In addition, there was no significant difference in the secondary outcome measures, improvement in the visual function measures and MRI, at any time during follow-up. Results showed no effect of IVIg on long-term visual function following acute optic neuritis, nor was there an effect of IVIg treatment in reducing latency on visual evoked potentials.

Ig has been proposed for treatment of neuromyelitis optica (NMO), which is a rare disease syndrome of the central nervous system (CNS) that affects the optic nerves and spinal cord. In the disease process of NMO the immune system cells and antibodies attack and destroy myelin cells in the optic nerves and the spinal cord. NMO leads to loss of myelin, which is a fatty substance that surrounds nerve fibers facilitating neural signals to move from cell to cell. NMO can also damage nerve fibers and leave areas of broken-down tissue. The cause of NMO is not clear. Individuals with NMO develop optic neuritis, which causes pain in the eye and vision loss. Spinal cord complications include transverse myelitis, which causes weakness, numbness, and sometimes paralysis of the arms and legs, along with sensory disturbances and loss of bladder and bowel control. There are no published clinical trials demonstrating efficacy of Ig treatment. Published literature consists of case reports and case series (Bakker, 2004; Ii, 2008; Okada,2007). 

Jordan and colleagues (2004) reported outcomes of a randomized, double-blind, placebo- controlled clinical trial for the reduction of anti-HLA antibody levels and improvement of transplant rates by intravenous immunoglobulin (IVIg). One hundred one participants with end stage renal disease (ESRD) and highly sensitized to HLA antigens (panel reactive antibody [PRA] greater than or equal to 50% monthly for 3 months) were enrolled in a National Institutes of Health (NIH) sponsored trial (IG02). Participants received either IVIg 2 gm/kg monthly for 4 months or an equivalent volume of placebo with additional infusions at 12 and 24 months after entry if not transplanted. If transplanted, additional infusions were given monthly for 4 months. Baseline PRA levels were similar in both groups. However, IVIg significantly reduced PRA levels in the IVIg group compared with placebo. Sixteen IVIg participants (35%) and eight placebo participants (17%) were transplanted. Rejection episodes occurred in 9 of 17 IVIg and 1 of 10 placebo subjects. Seven graft failures occurred (four IVIg, three placebo) among adherent participants with similar two year graft survival rates (80% IVIg, 75% placebo). With a median follow-up of 2 years after transplant, the viable transplants functioned normally. The authors concluded that IVIg is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized individuals with ESRD.

In a review, Jordan and colleagues (2011) addressed clinical applications of Ig in solid organ transplantation finding data suggesting that IVIg has a much broader ability to regulate cellular immunity and is a modifier of complement activation and injury. Published clinical data address the use of IVIg in desensitization and treatment of antibody-mediated rejection (AMR) and are supportive for use in kidney transplant recipients, but no clinical trials using IVIg in sensitized individuals have been performed. Additionally, the available data regarding the use of IVIg for desensitization and treatment of AMR in cardiac and lung allograft recipients is not conclusive. The authors pointed out that desensitization (immunomodulation) pre and post solid organ transplantation requires a coordinated approach so that AMR and infectious complications are minimized. There are currently no FDA approved drugs/protocols for desensitization.

Kobashigawa and colleagues (2009) reported recommendations from an international consensus conference addressing those who are sensitized and awaiting heart transplant. The 71 member panel examined diagnostic and treatment regimes from transplant centers and reached consensus for anti-HLA antibody screening and testing methodology. The desensitization recommendations pre transplant included IVIg, plasmapheresis, and possibly rituximab.

Kobashigawa and colleagues (2011) reported recommendations from an international consensus conference addressing antibody mediated rejection (AMR) in heart transplantation. The conference participants noted that the problem of AMR is due to the many different features of AMR making the current methods for diagnosis and treatment contentious. The panel examined diagnostic and treatment regimens from transplant centers and the published literature. In regards to the use of IVIg the conference recommendation was that the initial treatment for AMR may include high dose corticosteroids, plasmaperesis and IVIg.

A guideline addressing the use of Ig for sensitized individuals undergoing solid organ transplantation (SOT) was developed by the Canadian Blood Services and the National Advisory Committee of Blood and Blood Products of Canada and provides the following recommendations regarding non kidney solid organ transplantation:

Recommendation

• There is insufficient evidence to recommend for or against the routine use of IV Ig for desensitization for patients undergoing heart transplantation to improve graft/overall survival or to treat rejection; however, other factors may influence decision-making.
• There is insufficient evidence to make a recommendation for or against the routine use of IV Ig for desensitization for patients undergoing lung transplantation or for the treatment of rejection; however, other factors may influence decision-making.
• There is insufficient evidence to make a recommendation for or against the routine use of IV Ig for patients undergoing liver transplantation or for the treatment of rejection/ABO-incompatible liver transplantation.

The committee further stated that:

There is limited methodologically rigorous evidence for the use of IV Ig for solid organ transplantation. Future studies are needed to delineate the effect of IV Ig on desensitization using standardized methods for desensitization; the effect of IVIG on acute rejection rates, graft survival, and overall survival; the use of the combined modality IV Ig and PP compared either to PP or IV Ig alone; and the optimum dosage of IVIG. (Shehata, 2010)

The National Comprehensive Cancer Network^® (NCCN) clinical practice guidelines for Non-Hodgkin's Lymphoma (2011) addressed the use of Ig for recurrent sinopulmonary infections for those with CLL when the serum IgG levels are less than 500mg/dl.

Antibody: Specialized gamma globulin proteins found in the blood or lymph, and that act as an immune defense against foreign agents (antigens).

Antigen: A substance, that when introduced into the body stimulates the production of an antibody. Antigens include toxins, bacteria, foreign blood cells, and the cells of transplanted organs.

Standard deviation: A measure of variability from the average or mean. In laboratory testing results, the average may be expressed as one measurement or as a "reference range" for acceptable values between 2 measurements. The upper and lower measurements reported are usually 2 standard deviations from the mean.

Peer Reviewed Publications:

1. Abrahamian F, Agrawal S, Gupta S. Immunological and clinical profile of adult patients with selective immunoglobulin subclass deficiency: response to intravenous immunoglobulin therapy. Clin Exp Immunol. 2010; 159(3):344-350.
2. Achiron A, Barak Y, Miron S, Sarova-Pinhas I. Immunoglobulin treatment in refractory myasthenia gravis. Muscle Nerve. 2000; 23(4):551-555.
3. Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol. 2001; 45(6):825-835.
4. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 2001; 45:679-690.
5. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus foliaceus unresponsive to conventional therapy. J Am Acad Dermatol. 2002; 46:42-49.
6. Ancona KG, Parker RI, Atlas MP, Prakash D. Randomized trial of methylprednisolone versus intravenous immunoglobulin for the treatment of acute idiopathic thrombocytopenic purpura in children. J Ped Hematol Oncol. 2002; 24(7):540-544.
7. Bachot N, Revuz J, Roujeau J. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol. 2003; 139:33-36.
8. Bakker J, Metz L. Devic's neuromyelitis optica treated with intravenous gamma globulin (IVIG). Can J Neurol Sci. 2004; 31(2):265-267.
9. Cavaletti G. Current status and future prospective of immunointervention in multiple sclerosis. Curr Med Chem. 2006; 13(19):2329-2343.
10. Cherin P, Pelletier S, Teixeira A, et al. Results and long-term follow-up of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum. 2002; 46(2):467-474.
11. Dalakas MC, Fujii M, Li M, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. 2001; 345(26):1870-1876.
12. Darabi K, Abdel-Wahab O, Dzik WH. Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion. 2006; 46(5):741-53.
13. Engineer L, Ahmed AR. Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: analysis of current data. J Am Acad Dermatol. 2001; 44(1):83-88.
14. Engineer L, Bhol KC, Ahmed AR. Analysis of current data on the use of intravenous immunoglobulins in management of pemphigus vulgaris. J Am Acad Dermatol. 2000; 43(6):1049-1057.
15. Frohman L, Dellatorre K, Turbin R, Bielory L. Clinical characteristics, diagnostic criteria and therapeutic outcomes in autoimmune optic neuropathy. Br J Ophthalmol. 2009; 93(12):1660-1666. 
16. Genevay S, Saudan-Kister A, Guerne PA. Intravenous gammaglobulins in refractory polymyositis: lower dose for maintenance treatment is effective. Ann Rheum Dis. 2001; 60(6):635-636.
17. Gerschlager W, Brown P. Effect of treatment with Intravenous immunoglobulin on quality of life in patients with stiff-person syndrome. Movement Disord. 2002; 17(3):590-593.
18. Gold R, Stangel M, Dalakas MC. Drug Insight: the use of intravenous immunoglobulin in neurology-therapeutic considerations and practical issues. Nat Clin Pract Neurol. 2007; 3(1):36-44.
19. Hedlund-Treutiger I, Henter J, Elinder G. Randomized study of IVIG and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura. J Ped Hematol Oncol. 2003; 25(2):139-144.
20. Hughes R, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylatechromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized placebo-controlled trial. Lancet Neural. 2008; 7:136–144. 
21. Ii Y, Shindo A, Sasaki R, et al. Reversible stenosis of large cerebral arteries in a patient with combined Sjogren's syndrome and neuromyelitis optica spectrum disorder. Rheumatol Int. 2008; 28(12):1277-80.
22. Jolles S. Clinical uses of intravenous immunoglobulin. Clinical and Experimental Immunology. 2005; 142:1–11.
23. Jordan S, Cunningham-Rundles C, McEwan R. Utility of intravenous immune globulin in kidney transplantation:  Efficacy, safety, and cost implications. Am J of Transplantation. 2003; 3(6):653-664.
24. Jordan SC, Vo A, Bunnapradist S, et al. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation. 2003; 76(4):631-636.
25. Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011; 11(2):196-202.
26. Kobashigawa J, Mehra M, West L, et al. Report from a consensus conference on the sensitized patient awaiting heart transplantation. J Heart Lung Transplant. 2009; 28(3):213-225.
27. Kobashigawa J, Crespo-Leiro MG, Ensminger SM, et al. Report from a consensus conference on antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2011; 30(3):252-269.
28. Noseworthy JH, O'Brien PC, Petterson TM, et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology. 2001; 56(11):1514-1522.
29. Okada K, Tsuji S, Tanaka K. Intermittent intravenous immunoglobulin successfully prevent relapses of neuromyelitis optica. Intern Med 2007; 46:1671-1672.
30. Pescovitz M. Drugs for the hypersensitized patient. Current Opinion in Organ Transplantation. 2005; 10(4):279-283.
31. Petereit HF, Reske D, Pukrop R, et al. No effect of intravenous immunoglobulins on cytokine-producing lymphocytes in secondary progressive multiple sclerosis. Mult Scler. 2006; 12(1):66-71. 
32. Qureshi AI, Choudhry MA, Akbar M, et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology. 1999; 52(3):629-632.
33. Roed HG, Langkilde A, Sellebjerg F, et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology. 2005; 64(5):804-810.
34. Rose ME, Lang DM. Evaluating and managing hypogammaglobulinemia. Cleve Clin J Med. 2006;73(2):133-144.
35. Sami N, Bhol KC, Ahmen AR. Treatment of oral pemphagoid with intravenous immunoglobulins as monotherapy. Long term follow-up: Influence of treatment on antibody titers to human a6 integrin. Clin Exp Immunol. 2002; 129(3):533-540.
36. Sander H, Latov N. Research criteria for defining patients with CIDP.  Neurology 2003; 60(Suppl 3):S8–S15.
37. Saperstein DS, Katz JS, Amato AA, Barohn RJ. Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve. 2001; 24:311–324.
38. Selcen D, Dabrowski ER, Michon AM, Nigro MA. High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol. 2000; 22(1):40-43.
39. Shehata N, Palda VA, Meyer RM, et al. The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline. Transfus Med Rev. 2010; 24 Suppl 1:S7-S27.
40. Strasser-Fuchs S, Fazekas F, et al. The Austrian Immunoglobulin in MS (AIMS) study: final analysis. Mult Scler. 2000; 6 Suppl 2:S9-S13.
41. Teksam M, Tali T, Kocer B, Isik S. Qualitative and quantitative volumetric evaluation of the efficacy of intravenous immunoglobulin in multiple sclerosis: preliminary report. Neuroradiology. 2000; 42(12):885-889.
42. Wolfe GI, Barohn RJ, Foster BM et al. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve. 2002; 26(4):549-552.
43. Yarmohammadi H,  Estrella L, Doucette J, et al. Recognizing primary immune deficiency in clinical practice. Clinical and Vaccine Immunology. 2006; 13(3):329–332.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Academy of Allergy, Asthma and Immunology (AAAAI). Work Group Report on the appropriate use of intravenously administered immunoglobulin. 2005. Available at: http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and%20Parameters/IGIV-2005.pdf . Accessed on September 20, 2011.
2. American Academy of Neurology (AAN). Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the AAN AIDS Task Force. Neurology. 1991; 41(5):617-618.
3. American Academy of Otolaryngology–Head and Neck Surgery Foundation. Clinical practice guideline: Adult sinusitis. Otolaryngology–Head and Neck Surgery.  2007; 137:S1-S31.
4. Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD003313. DOI: 10.1002/14651858.CD003313.
5. American College of Obstetricians and Gynecologists (ACOG).Practice Bulletin No. 6, Sept 1999.
6. American Society of Health-System Pharmacists^® (AHFS) Hospital Formulary Service^® (AHFS). Immune Globulin. AHFS Drug Information 2011^®. Bethesda, MD.
7. Bonilla FA, Bernstein IL, Khan DA,  et al. American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94(5 Suppl 1):S1-63
8. Centers for Medicare and Medicaid Services. National Coverage Determination for Intravenous Immune Globulin for the Treatment of Autoimmune Mucocutaneous Blistering Diseases. NCD #250.3. Effective October 1, 2002. Available at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=158&ncdver=1&bc=AgAAQAAAAAAA& .  Accessed on June 20, 2011.
9. Centers for Medicare and Medicaid Services. National Coverage Determination for Lymphocyte Immune Globulin, Anti-Thymocyte Globulin (Equine). NCD# 260.7. Effective (longstanding national coverage determination). Available at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=148&ncdver=1&bc=AgAAQAAAAAAA& .  Accessed on June 20, 2011.
10. Donofrio PD, Berger A, Brannagan TH, et al. Consensus statement: The use of intravenous immunoglobulin in the treatment of neuromuscular conditions report of the AANEM AD HOC committee. American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). Muscle Nerve. 2009; 40: 890–900.
11. Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD002277. DOI: 10.1002/14651858.CD002277.pub2.
12. Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58:169-178. Reaffirmed July 19, 2008..
13. Hughes RA, Bouche P, Cornblath DR, et al. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2006; 3(4):326-332.
14. Hughes RAC, Raphaël J-C, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD002063. DOI: 10.1002/14651858.CD002063.pub3.
15. Immune Serum Globulin. In: DrugPoints^® System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on June 20, 2011.
16. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of paraproteinemic demyelinating neuropathies. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Soc. J Peripher Nerv Syst 2006; 11(1):9-19. Available at: http://www.guidelines.gov/summary/summary.aspx?ss=15&doc_id=9656&nbr=&string=#s28 . Accessed on June 20, 2011. 
17. Lunn MPT, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD002827. DOI: 10.1002/14651858.CD002827.pub2.
18. NCCN Clinical Practice Guidelines in Oncology™. © 2011 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org/index.asp. Accessed on July 5, 2011.
    • Non-Hodgkin's Lymphomas. (V.3.2011). Revised May 8, 2011.
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20. National Institutes of Health (NIH). National Institute of Neurological Disorders and Stroke (NINDS). NINDS Neuromyelitis Optica Information Page. 2010. Available at: http://www.ninds.nih.gov/disorders/neuromyelitis_optica/neuromyelitis_optica.htm.  Accessed on November 30, 2011.
21. Oates-Whitehead RM, Baumer JH, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD004000. DOI: 10.1002/14651858.CD004000.
22. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD000361. DOI: 10.1 002/ 14651858.CD000361.pub2.
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26. van Schaik IN, van den Berg LH, de Haan R, Vermeulen M. Intravenous immunoglobulin for multifocal motor neuropathy. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD004429. DOI: 10.1002/14651858.CD004429.pub2.
27. U.S. Food and Drug Administration (FDA). Center for Biologics Evaluation and Research. Product approval: Gammaplex^®_. Available at: http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs
    /FractionatedPlasmaProducts/ucm182874.htm. Accessed on June 20, 2011.
28. U.S. Food and Drug Administration (FDA). Center for Biologics Evaluation and Research. Product approval: Hizentra^®_. Available at: http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs
    /FractionatedPlasmaProducts/ucm202630.htm. Accessed on June 20, 2011.

Carimune^®
Flebogamma^®
Gammagard^®
Gammaplex^®
Gamunex^®
GamaSTAN^®
Hizentra^®
Immune Globulin
Intravenous Immune Globulin, Human (IVIg)
IVIg
Octagam^®
Panglobulin^®
Polygam^®
Privigen^®
Vivaglobin^®

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.