Coverage Policy Manual
Policy #: 1997113
Category: Pharmacy
Initiated: October 1993
Last Review: October 2018
  Immune Globulin, Intravenous and Subcutaneous

Description:
Human immune globulin replacement therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral antigens. Three formulations of human IgG are available for delivery by intravenous infusion (IVIg), by subcutaneous infusion (SCIg), or by intramuscular (IMIg) depot injections. IMIg has been largely abandoned in the U.S. because volume constraints and pain preclude delivery of sufficient product weekly into each buttock to yield therapeutic serum levels of IgG, leaving recipients susceptible to infections.
 
IVIg is an antibody-containing solution obtained from the pooled plasma of healthy blood donors that contains antibodies to greater than 10 million antigens. IVIg has been used to correct immune deficiencies in patients with either inherited or acquired immunodeficiencies and has also been investigated as an immunomodulator in diseases thought to have an autoimmune basis.  Several IVIg products are available for clinical use in the U.S.  This policy only addresses nonspecific pooled preparations of IVIg, including Gammagard (Baxter), Gamimune (Bayer), Sandoglobulin (Sandoz), Iveegam (Immuno), Venoglobulin (Alpha Therapeutics), Gammar (Centeon), and Polygam (American Red Cross). This policy DOES NOT address other immunoglobulin preparations that are specifically used for passive immunization to prevent or attenuate infection with specific viral diseases such as respiratory syncytial virus, cytomegalovirus, or hepatitis B.
 
One IVIG product (Gamunex) received FDA approved indication for treatment of chronic Inflammatory demyelinating polyneuropathy in September 2008 (FDA, 9/12/08).
 
Subcutaneous infusion immune globulin is used for treating patients with primary immunodeficiencies (PID). A genetic basis for more than 80 different types of PID has been discovered, the most common being primary antibody deficiency (PAD) that is associated with low levels or total lack of normal circulating immunoglobulins. The first FDA-approved SCIg product, Vivaglobin, is a pasteurized, polyvalent human normal immune globulin product that is manufactured from large pools of human plasma by cold alcohol fractionation with no chemical or enzymatic alterations. Vivaglobin administration produces relatively stable steady-state serum levels of IgG that are representative of those seen in a normal human population. Applications of this product for conditions other than primary immunodeficiencies are considered off-label in the United States and are not addressed in this policy. In recent years, other SCIg products have also received FDA-marketing approval.
 
Regulatory Status
Several IVIg products have been approved by FDA. These include Carimune® (ZLB Bioplasma), Flebogamma® (Grifols), Gammagard® (Baxter), Gamunex-C® (Grifols), Octagam® (Octapharma), Polygam® S/D (Baxter) Privigen® (CSL Behring), and BIVIGAM™ (Biotest Pharmaceuticals).
At least 1 IVIg product is FDA-approved to treat the following conditions:
  • Primary Humoral Immunodeficiency
  • Multifocal Motor Neuropathy
  •  B-cell Chronic Lymphocytic Leukemia
  • Immune (aka Idiopathic) Thrombocytopenic Purpura
  •  Kawasaki syndrome
  • Chronic Inflammatory Demyelinating Polyneuropathy
 
Several SCIg products have received FDA marketing approval for primary immunodeficiencies. These include Vivaglobin® (ZLB Behring, Kankakee, IL, discontinued by the company in 2013), Hizentra® (ZLB Behring, Kankakee, IL), Gamunex-C® (Grifols), and Gammaked® (Kedrion Biopharma, Cambridge, MA).
 
Coding
There are CPT and HCPCS codes that describe IVIg and SCIg products:
90283: Immune globulin (IgIV), human, for intravenous use
90284:  Immune globulin (SCIg), human, for use in subcutaneous infusions, 100 mg, each
J1459:  Injection, immune globulin (Privigen), intravenous, non-lyophilized (eg, liquid), 500 mg
J1557:  Injection, immune globulin (Gammaplex), intravenous, non-lyophilized (eg, liquid), 500 mg
J1556: Injection, immune globulin (bivigam), 500 mg
J1559   Injection, immune globulin (Hizentra), 100 mg
J1561:  Injection, immune globulin (Gamunex-C/Gammaked), non-lyophilized (eg, liquid), 500 mg
J1562:  Injection, immune globulin (Vivaglobin), subcutaneous, 100 mg
J1566:  Injection, immune globulin, intravenous, lyophilized (eg, powder), not otherwise specified, 500 mg
J1568:  Injection, immune globulin (Octagam) intravenous, non-lyophilized (eg, liquid), 500 mg
J1569:  Injection, immune globulin (Gammagard Liquid) intravenous, non-lyophilized (eg, liquid), 500 mg
J1572:  Injection, immune globulin (Flebogamma/Flebogamma DIF), intravenous, non-lyophilized (eg, liquid), 500 mg
J1575  Injection, immune globulin/hyaluronidase, 100 mg immunoglobulin
J1599:  Injection, immune globulin, intravenous, non-lyophilized (eg, liquid), not otherwise specified, 500 mg
 
The following CPT drug administration codes would be used for the administration of these products:
96365-96366 for intravenous infusions; and
96369-96371 for subcutaneous infusions
 

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
SUBCUTANEOUS IMMUNOGLOBULIN
 
SCIg may meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of primary immunodeficiencies, including:
 
    • congenital agammaglobulinemia,
    • hypogammaglobulinemia,
    • common variable immunodeficiency (CVID),
    • severe combined immunodeficiency,
    • Wiskott-Aldrich syndrome,
    • X-linked agammaglobulinemia (XLA); OR
    • when coverage criteria have been met for intravenous immune globulin (IVIG) but patient is unable to tolerate IVIG because of side effects from the IVIG treatment.
 
INTRAVENOUS IMMUNOGLOBULIN (FDA APPROVED INDICATIONS)
 
The administration of intravenous immune globulin meets member benefit certificate primary coverage criteria for effectiveness for the following FDA approved indications:
 
    • Congenital Agammaglobulinemia (X-linked agammaglobulinemia)
    • Common Variable Immunodeficiency (panhypogammaglobulinemia)
    • X-linked immunodeficiency hyperimmunoglobulin IgM
    • X-linked hyper-IgM syndrome and ataxia telangiectasia  (Effective January 2017)
    • Severe Combined Immunodeficiency
    • Wiskott-Aldrich Syndrome
    • Bone marrow transplantation: to prevent risk of acute graft-versus-host disease, associated interstitial pneumonia (infectious or idiopathic), and infections (e.g., CMV, varicella-zoster viral infection, and recurrent bacterial infection) after allogeneic bone marrow transplantation in patients 20 years of age or older in the first 100 days after transplantation;
    • Chronic inflammatory demyelinating polyneuropathy (FDA approved indication) when all of the following criteria are documented:
      • Progressive or relapsing motor AND sensory dysfunction of more than one limb; AND
      • Significant disability in arm or leg function developing over at least two months; AND
      • Hypo- or areflexia; AND
      • One of the following:
        • partial conduction block or abnormal temporal dispersion of conduction must be present in at least 2 nerves and there must be significantly reduced conduction velocity, or significantly prolonged distal motor latency, or absent or significantly prolonged minimum Fwave latency in at least one other nerve; OR
        • in the absence of block or dispersion, significantly reduced conduction velocity, or significantly prolonged distal motor latency, or absent or significantly prolonged minimum F-wave latency must be present in at least 3 nerves; OR
        • in the presence of significant neurophysiologic abnormalities in only 2 nerves, unequivocal histological evidence of demyelinated nerve fibers in a nerve biopsy must also be present. CSF Studies are encouraged. An elevated protein with a CSF white count of <10/mm3 in HIV-1 negative patients would be expected in patients with CIDP.
    • Chronic Lymphocytic Leukemia with associated hypogammaglobulinemia in patients (FDA approved indication) who have demonstrated frequent and recurrent bacterial infections or who demonstrate impaired response to bacterial polysaccharides or proteins (study results);
    • Human immunodeficiency virus infection (HIV) in children to decrease the risk of serious bacterial infection (FDA approved indication). IVIG is covered only in children who have IgG less than 400 mg/dL or functional antibody deficiency is demonstrated by poor specific antibody titers or recurrent bacterial infections (ACIP, AAP, CDC, NIH, IDSA, PIDS recommendation).
    • Idiopathic thrombocytopenic purpura, acute, or chronic, when a rapid rise in the platelet count is required, such as prior to surgery or to prevent/control excessive bleeding (FDA approved indication) when the platelet count is less than 30,000 (study results).
    • Kawasaki’s Disease (Mucocutaneous lymph node syndrome) when used in conjunction with ASA and treatment is started within the first 10 days of illness (FDA approved indication) or as soon as possible after the disease is diagnosed or strongly suspected (AAP, AHA, ACCP recommendation);
    • Multifocal Motor Neuropathy (MMN) when used as initial and maintenance therapy to improve muscle strength and disability in adult patients. (EFFECTIVE June 2013)
    • Toxic Shock Syndrome  
    • Patients with antiphospholipid syndrome. (Effective January 2017)
 
OFF LABEL INDICATIONS FOR INTRAVENOUS IMMUNOGLOBULIN
 
These off label indications are considered eligible for coverage based on one or more of the following:
    • High quality systematic reviews of randomized controlled trials by independent review organizations (e.g., Cochrane Systematic Reviews, AHRQ Evidence Based Practice Centers);
    • adequately powered randomized controlled trials published in peer-reviewed medical literature;
    • single or multiple randomized controlled trials, adequately populated, with risk of bias, but recommended in publications in peer-reviewed journals;
    • prospective, non-randomized, adequately populated case-control or cohort study(s) with low risk of confounding or bias;
    • expert opinion, presented as published position papers by national medical societies supporting this opinion (unless in conflict with other expert opinion); and
    • rare life threatening conditions for which:  only case series have been reported in peer reviewed medical literature; more than one series has reported significant, lasting improvement; no conflicting evidence is known; and because of the rarity of the condition, adequate appropriate trials would be unlikely.  
 
There is no coverage for IVIG for indications other than those specifically listed as covered; requests for coverage of conditions not listed in the covered section should be submitted for review, and include references from peer reviewed journals which support coverage for the proposed condition.
 
Off-label use of IVIG Meets Member benefit certificate primary coverage criteria for the following conditions:
 
    • Acquired Factor VIII Deficiency/Acquired Hemophilia for patients unresponsive to, or cannot tolerate, standard therapy
    • Acquired hypogammaglobulinemia associated with hematological malignancy in patients with recurrent bacterial/fungal infection, and/or who have no antibody response to immunization with bacterial antigen
    • Acquired hypogammaglobulinemia following solid organ transplant in patients who have recurrent bacterial/fungal infection
    • Anti-neutrophil cytoplasmic antibody vasculitis (e.g., Wegener’s granulomatosis, Churg-Strauss syndrome) that has not responded to standard therapy)
    • Autoimmune encephalopathy (e.g., Hashimoto’s encephalopathy, voltage-gated potassium channel complex antibody-associated encephalopathy, progressive encephalomyelopathy) in patients refractory to, or cannot tolerate, glucocorticoids
    • Autoimmune hemolytic anemia, warm type, that has not responded to standard therapy
    • Autoimmune hemolytic anemia, life threatening
    • Autoimmune hemolytic anemia, neonatal
    • Autoimmune, non-paraneoplastic, encephalopathy (Hashimoto’s encephalopathy, voltage-gated potassium channel antibody encephalopathy),  refractory to standard therapy (Effective, Nov 2011)
    • Autoimmune retinopathy
    • Dermatomyositis, refractory to glucocorticoids and at least one other immunosuppressant drug.  There must be laboratory confirmation that the patient does not have inclusion body myositis. Coverage for more than four months will require documentation of response to IVIG
    • Encephalitis, acute disseminated, refractory to corticosteroid therapy
    • End-Stage Renal Disease who have been on a transplant waiting list for 2 years and are otherwise eligible for transplantation but have been unable to find a suitable donor because of high, unacceptable levels of anti-HLA Panel Reactive Antibodies (>=50%).  The dose covered is 2g/kg of body weight per month for 3 months.
    • Fetal/maternal red blood cell alloimmunization
    • Good Syndrome (Durable Hypogammaglobulinemia Associated with Thymoma) (Effective, April 2012)
    • Graves ophthalmopathy, refractory to standard therapy
    • Guillain-Barre, within 2-weeks of symptom onset
    • Guillain-Barre, relapse occurring following initial response to IVIG
    • Hemolytic disease of newborn with hyperbilirubinemia (Neonatal Iso-immune hemolytic jaundice) when there is parental refusal for exchange transfusion or where appropriate blood components for exchange transfusion are unavailable
    • Hemolytic transfusion reaction, acute, severe, refractory to standard therapy
    • Hemolytic transfusion reaction in sickle cell disease, life threatening
    • Hemolytic uremic syndrome in adults, refractory to standard therapy
    • Hemolytic uremic syndrome, children, refractory to standard therapy
    • Hyperimmunoglobulin E syndrome
    • Hyperimmunoglobulin M syndrome, X-linked, or autosomal recessive (Effective, April 2012)
    • IgG subclass deficiency only when there is also a demonstrated deficiency in the ability to form antibodies against a variety of polysaccharide AND protein antigens
    • IgG/IgA Gammopathy of Unknown Significance, with polyneuropathy
    • IRAK4 Immunodeficiency, homozygous or compound heterozygous (Effective, March 2012)
    • Isaac’s Syndrome (Neuromyotonia), refractory to standard treatment
    • Lupus Erythematosus, refractory to standard treatment  
    • Multiple Myeloma, in patients with recurrent infections who are unable to respond to pneumococcal vaccine (as demonstrated by absence of or low titer to pneumococcal vaccine, determined by serological studies)
    • Multiple Myeloma, in patients who are post hematopoietic stem cell transplant, who have hypogammaglobulinemia (IgG < 400 mg/dL), who have had two documented (significant) bacterial infections
    • Multiple Sclerosis, Marburg disease
    • Multiple Sclerosis, acute optic neuritis
    • Multiple Sclerosis, relapsing-remitting type only, when interferon therapy has failed.  Coverage requires written documentation
    • Myasthenia Gravis, Juvenile, refractory to standard treatment
    • Myasthenia Gravis, Juvenile, refractory to standard treatment, for maintenance [Dosing regimen: IVIG loading dose given at 1g/kg body weight for 1 to 2 daily treatments and then 1 treatment every 2 to 3 weeks, followed by a gradual taper to complete withdrawal as tolerated].
    • Myasthenia Gravis, Neonatal, refractory to standard treatment
    • Myasthenia Gravis, one or two doses for the treatment of acute crisis or worsening of disease unresponsive to conventional therapy.
    • Myasthenia Gravis, refractory to standard treatment, for maintenance [Dosing regimen: IVIG loading dose given at 2G/Kg and then as booster doses of 0.4K/kg every 4-12 weeks, as necessary.]  
    • Myasthenia Gravis, Stabilization Prior to Surgery
    • Opsoclonus-Myoclonus Syndrome, refractory to standard therapy
    • Paraneoplastic Retinopathy (Cancer Associated Retinopathy; Melanoma Associated Retinopathy)
    • Paraneoplastic Syndrome (Lambert-Eaton myasthenia), refractory to standard therapy
    • Parvovirus B19 in members with anemia who are immunodeficient or who have sickle cell disease.  
    • Pemphigus & Other Autoimmune Blistering Diseases refractory to standard therapy
    • Polymyositis, refractory to standard therapy
    • Post-transfusion Purpura
    • Pure Red Cell Aplasia (PRCA), refractory to standard therapy
    • Stevens-Johnson Syndrome
    • Stiff-person syndrome
    • Thrombocytopenia, Alloimmune, Neonatal
    • Thrombocytopenia, HIV associated
    • Thrombocytopenic Purpura, Idiopathic, Acute, Adult, with acute bleeding
    • Thrombocytopenic Purpura, Idiopathic, Acute, Adult, Severe (platelets less than 30,000), without bleeding, refractory to standard therapy
    • Thrombocytopenic Purpura, Idiopathic, Children, platelets less than 30,000, or with acute bleeding, refractory to standard therapy
    • Thrombocytopenic Purpura, Idiopathic, to allow patient to undergo surgery
    • Thrombotic Thrombocytopenic Purpura, refractory to standard therapy
    • Toxic Epidermal Necrolysis
    • Transient Hypogammaglobulinemia of Childhood (Effective, April 2012)
    • Transplant, Kidney, End-Stage Renal Disease, on transplant waiting list for 2 years and are otherwise eligible for transplantation but have been unable to find a suitable donor because of high, unacceptable levels of anti-HLA Panel Reactive Antibodies (>=50%)
    • Transplant, Kidney, undergoing rejection due to pathologically demonstrated vascular rejection (February 2012)
    • Transplant, following solid-organ transplant, treatment of antibody-mediated rejection. A total dose of 2g/kg is covered. (Revised December 2013)
    • Transplant, prior to solid organ transplant, treatment of patients at high risk of antibody-mediated rejection, including highly sensitized patients and those receiving an ABO incompatible organ.  A total dose of 2 g/kg is covered. (Effective December, 2013)
    • Von Willebrand Disease, Acquired, refractory to standard therapy;  not covered for routine use
    • West Nile Virus Encephalomyelitis, as treatment and not prophylaxis (Effective, March 2012)
    • West Syndrome, refractory to standard therapy
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
IVIG  does not meet member benefit certificate primary coverage criteria for effectiveness, or is considered investigational for those contracts without primary coverage criteria including but not limited to the following off label uses:
 
    • Adrenoleukodystrophy (lack of evidence of effectiveness – absence of clinical trials; conflicting case reports; expert opinion recommends against)
    • Alzheimer’s Disease (lack of evidence of effectiveness – absence of clinical trial outcomes; IVIG for Alzheimer’s disease is presently being studied in clinical trials to determine safety and effectiveness; expert opinion recommends against)
    • Amyotrophic Lateral Sclerosis (lack of evidence of effectiveness – absence of clinical trials; expert opinion recommends against)
    • Aplastic Anemia (lack of evidence of effectiveness – absence of clinical trials; conflicting case reports; expert opinion recommends against)
    • Asthma (lack of evidence of effectiveness – randomized controlled trials described no benefit; expert opinion recommends against)
    • Autism (lack of evidence of effectiveness – absence of clinical trials; case reports show conflicting results; expert opinion recommends against)
    • Autism, Oral Human Immunoglobulin for Associated Gastrointestinal Symptoms (lack of evidence of effectiveness – randomized controlled trial described no benefit)
    • Autoimmune Urticaria/Angioedema (lack of effectiveness – absence of clinical trials)
    • Birdshot Retinopathy (Effective July 2013)
    • Cardiomyopathy, Idiopathic  (lack of evidence of effectiveness – randomized controlled trial described no benefit)
    • Chronic Fatigue Syndrome (lack of evidence of effectiveness – randomized controlled trial described no benefit; expert opinion recommends against)
    • Clostridium difficile enterocolitis (lack of evidence of effectiveness – no trials establishing benefit; mixed results from uncontrolled studies)
    • Congenital Heart Block, In Utero, to prevent progression of 1st or 2nd degree heart block to complete heart block (lack of evidence of effectiveness – no trials establishing benefit, and conflicting evidence from rare case reports)
    • Congenital Heart Block, In Utero, to prevent heart block in the fetus of a mother with fetal heart block in an earlier pregnancy (lack of evidence of effectiveness – randomized controlled trials have shown no benefit)
    • Diabetes Mellitus (lack of evidence of effectiveness – randomized controlled trial described no benefit; not recommended by any appropriate medical society)
    • Diabetic Amyotrophy (lack of evidence of effectiveness – lack of clinical trials; expert opinion recommends against)
    • DiGeorge Syndrome (lack of evidence of effectiveness – expert opinion recommends against)
    • Epidermolysis Bullosa Acquisita (Effective July 2013)
    • Fisher Syndrome (lack of evidence of effectiveness – lack of clinical trials; expert opinion recommends against)
    • Hemophagocytic syndrome (i.e., hemophagocytic lymphohistiocytosis)
    • Inclusion Body Myositis (lack of evidence of effectiveness – randomized controlled trials described no benefit; expert opinion recommends against)
    • In-Vitro Fertilization Failure
    • MYD88 gene immunodeficiency, homozygous or compound heterozygous mutations (lack of evidence of effectiveness – expert opinion does not recommend)
    • Neonatal sepsis (lack of evidence of effectiveness – randomized trials showed no benefit; Cochrane Review concluded no benefit)
    • Necrotizing Fasciitis (Effective July 2013)
    • Polyradiculoeruopathy (other than CIDP) Effective July 2013)
    • Post-Cardiac Transplant Hypogammaglobulinemia (lack of evidence of effectiveness – presently under study in clinical trial)
    • Post-Polio Syndrome
    • Prevent Recurrent Pregnancy Loss associated with Anti-Phospholipid Antibody Syndrome (lack of evidence of effectiveness – randomized trials described no benefit; expert opinion recommends against)
    • Prevent Recurrent Pregnancy Loss in Unselected Pregnancy – (lack of evidence of effectiveness – randomized trials described no benefit; expert opinion recommends against)
    • Rheumatic Fever, Acute (lack of evidence of effectiveness – randomized trial described no benefit; expert opinion recommends against  
    • Rippling muscle disease, no medical literature reporting use of IVIG identified. (EFFECTIVE June, 2013)
 
There is no coverage for IVIG for indications other than those specifically listed as covered based on primary coverage criteria for effectiveness.
 
EFFECTIVE prior to July 2012
The administration of intravenous immune globulin meets primary coverage criteria for effectiveness and is covered for the treatment [to replace or boost immunoglobulin G (IgG)] of patients with primary immunodeficiency syndromes such as:
        • congenital agammaglobulinemia (X-linked agammaglobulinemia)
        • common variable immunodeficiency (panhypogammaglobulinemia)
        • X-linked immunodeficiency hyperimmunoglobulin M
        • severe combined immunodeficiency, and
        • Wiskott-Aldrich syndrome.
        • Coverage for hypogammaglobulinemia requires the demonstration of frequent bacterial infections, and demonstration that the patient is unable to form antibodies against a variety of polysaccharide and protein antigens (e.g., pneumococcal vaccine).
            • The usual dose for treatment of hypogammaglobulinemia or common variable immunodeficiency is 200-400 mg/kg once monthly.  A dose exceeding 400 mg/kg monthly, or an administration interval of less than four weeks, must be justified by documentation of subtherapeutic trough serum IgG levels
        •  Idiopathic thrombocytopenic purpura when a rapid rise in the platelet count is required, such as prior to surgery or to prevent/control excessive bleeding when the platelet count is less than 30,000;
        • Myasthenia gravis, one or two doses for the treatment of acute crisis or worsening of disease unresponsive to conventional therapy. This will require documentation of therapy regimens and responses to these regimens.  
        • Chronic IVIG administration is not covered for Acute inflammatory polyneuropathy (Guillain-Barré syndrome) when administered within the first 2  weeks after symptoms appear;
        • Chronic inflammatory demyelinating polyneuropathy when all of the following criteria are documented:
            • Progressive or relapsing motor AND sensory dysfunction of more than one limb; significant disability in arm or leg function developing over at least two months
            • Hypo- or areflexia
            • One of the following:
                • partial conduction block or abnormal temporal dispersion of conduction must be present in at least 2 nerves and there must be significantly reduced conduction velocity, or significantly prolonged distal motor latency, or absent or significantly prolonged minimum F-wave latency in at least one other nerve; OR
                • in the absence of block or dispersion, significantly reduced conduction velocity, or significantly prolonged distal motor latency, or absent or significantly prolonged minimum F-wave latency must be present in at least 3 nerves; OR
                • in the presence of significant neurophysiologic abnormalities in only 2 nerves, unequivocal histological evidence of demyelinated nerve fibers in a nerve biopsy must also be present.    CSF Studies are encouraged.  An elevated protein with a CSF white count of <10/mm3 in HIV-1 negative patients would be expected in patients with CIDP.
        • Autoimmune Mucocutaneous Blistering Diseases.
        • Mucocutaneous lymph node syndrome (Kawasaki's syndrome) when used in conjunction with ASA and treatment is started within the first 10 days of illness;
        • Dermatomyositis and polymyositis  refractory to corticosteroids and at least one other immunosuppressant drug.  There must be laboratory confirmation that the patient does not have inclusion body myositis. Coverage for more than four months will require documentation of response to IVIG;
        • Multiple Myeloma in patients with recurrent infections who are unable to respond to pneumococcal vaccine (as demonstrated by absence of or low titer to pneumococcal vaccine, determined by serological studies.) Coverage requires written documentation  reviewed by the Medical Director.  
        • Multiple myeloma patients who are post hematopoietic stem cell transplant, who have hypogammaglobulinemia (IgG < 400 mg/dL), who have had two documented (significant) bacterial infections;
        • Hypogammaglobulinemia with Chronic Lymphocytic Leukemia in patients who have demonstrated frequent and recurrent bacterial infections;
        • Multiple Sclerosis, relapsing-remitting type only, when interferon therapy has failed.  Coverage requires written documentation;
        • Multifocal motor neuropathy in patients with anti-GM1 antibodies and conduction block;
        • Bone marrow transplantation:  to prevent risk of acute graft-versus-host disease, associated interstitial pneumonia (infectious or idiopathic), and infections (e.g.,  CMV, varicella-zoster viral infection, and recurrent bacterial infection) after allogeneic bone marrow transplantation in patients 20 years of age or older in the first 100 days after transplantation;
        • Treatment of chronic parvovirus B19 in members with anemia who are immunodeficient or who have sickle cell disease.  Documentation of the patient's condition and reports of testing for the virus will be necessary for the claim to be reviewed.  
        • Treatment of hyperimmunoglobulin E syndrome;
        • Patients with End-Stage Renal Disease who have been on a transplant waiting list for 2 years and are otherwise eligible for transplantation but have been unable to find a suitable donor because of high, unacceptable levels of anti-HLA Panel Reactive Antibodies (>=50%).  The dose covered is 2g/kg of body weight per month for 3 months.
        • Treatment of antibody-mediated rejection within the first six weeks post renal transplant when used in conjunction with plasmapheresis.;
        • Treatment of stiff-person syndrome.  
        • Treatment of autoimmune hemolytic anemia, warm type, that has not responded to alternative therapy;
        • Treatment of children with human immunodeficiency virus infection, to decrease the risk of serious bacterial infection.  This is covered only in children who are not receiving co-trimoxazole as prophylaxis and for children with a CD4 count greater than 200-400;
        • Treatment of IgG subclass deficiency only when there is also a demonstrated deficiency in the ability to form antibodies against a variety of polysaccharide AND protein antigens.
 
 
There is no coverage for IVIG for indications other than those specifically listed as covered based on primary coverage criteria for effectiveness.

Rationale:
Given the heterogeneous nature and relapsing-remitting course of many of the diseases for which IVIg has been investigated as therapy, randomized, controlled trials (RCTs) are important for evaluating true benefit. However, in the case of rare disease, RCTs may be neither likely nor feasible. In these cases, reports of series data from at least 10 patients and consistent trends in results may support conclusions. Aside from the labeled indications, the use of IVIg has been investigated in a variety of diseases as follows:
 
ACQUIRED FACTOR VIII DEFICIENCY/ACQUIRED HEMOPHILIA
Acquired factor VIII deficiency/Acquired hemophilia is a coagulopathy caused by the development of autoantibodies directed against specific domains of the coagulation Factor VIII molecule.  Factor VIII becomes bound in the coagulation cascade which results in bleeding.  Mortality rates as high as 21% have been reported.  There are no randomized trials, and standard therapy, based on a randomized trial has been corticosteroids and cyclophosphamide (Green, 1993).  Cyclosporine has been substituted because of side of effects of long-term corticosteroid + cyclophosphamide.  Treatment with IVIg has been reported in case series (Bossi, 1998), but a meta-analysis of 245 patients with acquired Factor VIII hemophilia found that IVIG had a poor complete response rate (Delgado, 2003).  A protocol consisting of antibody depletion through immunoadsorption, IVIG, immunosuppression, and high dose factor VIII supplementation, reported in 2005, described 35 patients with an 88% long-term response rate (93% if 5 patients with malignancy were excluded) (Modified Bonn-Malmö Protocol) (Zeitler, 2005).   Neither the AHFS nor the Clinical Pharmacology Online drug compendia recommend IVIG for treatment of acquired hemophilia.  The Canadian Expert Panel on IVIG for hematological uses and the Academy of Allergy and Immunology Expert Panel on IVIG recommend IVIG for treatment of acquired hemophilia if standard therapy has failed.
 
ADRENOLEUKODYSTROPHY
X-linked adrenoleukodystrophy is an inborn error of peroxisomal metabolism characterized by progressive demyelination of the CNS and by hypoadrenalism.  There is very little information on the use of IVIG for adrenoleukodystrophy, and those results are conflicting (Miike, 1989; Cappa, 1994).  The Canadian IVIG Hematology & Neurology Expert Panel (Robinson, 2007) and the American Academy of Allergy, Asthma, and Immunology (Orange, 2006) recommend against the use of IVIG in adrenoleukodystrophy.
 
ALZHEIMER’S DISEASE
Antibodies against beta-amyloid have been found in human immunoglobulin preparations, leading to potential use of IVIG as treatment of Alzheimer’s disease.  A claims based retrospective review of IVIg for Alzheimer’s disease was published in 2009 (Fillit H) showed that previous treatment with IVIG was associated with a reduced risk of development of Alzheimer’s and related disorders in patients greater than or equal to 65 years of age.  No review articles recommend IVIG treatment of Alzheimer’s disease.  Use of IVIG for Alzheimer’s disease is being studied in clinical trials to determine safety and effectiveness (NCT00818662, NCT00299988, NCT00812565).   
 
AMYOTROPHIC LATERAL SCLEROSIS
Small prospective case series showed no benefit of IVIG for treatment of ALS (Dalakas, 1994; Meucci, 1996).   The Canadian IVIG Hematology & Neurology Expert Panel (Robinson, 2007) and the American Academy of Allergy, Asthma, and Immunology (Orange, 2006) recommend against the use of IVIG in adrenoleukodystrophy.
 
APLASTIC ANEMIA
There have been no clinical trials on IVIG for aplastic anemia.  Rare case reports (Sadowitz, 1990; Chen, 1995) and letters to the editor (Bodenstein, 1991) have described benefit, but other studies have shown no benefit (Miceli, 1990; Sumimoto, 1992; Bejaoui, 1993).  The Canadian IVIG Hematology & Neurology Expert Panel (Robinson, 2007) recommends against IVIG for aplastic anemia.  Neither the AHFS nor Clinical Pharmacology Online drug compendia recommend use of IVIG in aplastic anemia.
 
ASTHMA
There have been 3 double-blind, placebo-controlled studies of IVIG in asthma (Niggemann, 1998;).  Two of the 3 showed no significant improvement (Kishiyama, 1999; Salum, 1999), and the third reported significant steroid-sparing effect in a subgroup that required relatively high daily doses of oral steroids.  The American Academy of Allergy and Immunology expert panel recommends against the use of IVIG for asthma (Orange, 2006).  Neither the AHFS nor the Clinical Pharmacology Online compendia recommend IVIG for asthma.  
 
AUTISM
There are no clinical trials reported on the use of IVIG to treat the neurological effects of autism, nor are there any ongoing trials of IVIG for autism listed on clinicaltrial.gov. (Oct 2010).  A randomized controlled trial of IVIG given orally for treatment of gastrointestinal symptoms of associated with autism has been reported.  This trial (NCT00110708) found no benefit (Handen, 2009).  An uncontrolled, unblinded study of 10 autistic children who received IVIG showed benefit in one child (Plioplys, 1998).  A brief report of a pilot trial described no benefit (DelGiudice-Asch, 1999).  The  American Academy of Allergy, Asthma & Immunology expert panel (Orange, 2006), and the Canadian IVIG Hematology & Neurology Expert Panel (Robinson, 2007) recommend against IVIG for autism.
 
AUTOIMMUNE BLISTERING DISEASES, INCLUDING PEMPHIGUS
Corticosteroids and immunosuppressive agents are considered first line therapy. IVIG therapy is the preferred therapy for patients who are resistant, nonresponsive, have contraindications, or develop serious catastrophic adverse effects (Ahmed, 2003).  No clinical trials have been reported for IVIG for pemphigus or other autoimmune blistering diseases.  Two randomized controlled trials are listed on clinicaltrial.gov.  NCT00483119 is an ongoing FDA sponsored trial at NYU Medical Center, initiated in 2007 with estimated completion date of 2011, comparing IVIG versus IVIG plus cyclophosphamide in patients with pemphigus that are not responding to, or have developed complications from, standard therapy.  A second study, in Japan (NCT00809822) recently completed but unreported, is a randomized, placebo controlled trial of IVIG for patients with bullous pemphigoid unresponsive to corticosteroids.   Prospective, non-randomized. open label clinical studies on patients who are unresponsive to corticosteroids and immunosuppressive agents have shown response to IVIG (Toth, 1999; Engineer, 2000; Ahmed, 2001; Sami, 2002; Bystryn, 2002; Baum, 2002; Ahmed, 2002).  IVIG has not been compared to newer biologics (e.g., anti-tumor necrosis alfa drugs).
 
AUTOIMMUNE ENCEPHALOPATHY
This condition was originally designated in 1966 as “Hashimoto’s encephalopathy”, but more recently has been termed “autoimmune encephalopathy” (Caselli, 2010; Flanagan, 2010).  There are few reports of this disease, and treatment has been with glucocorticoids.  A few case reports of IVIG for steroid refractory disease have indicated both acute and longer-term benefit from IVIG (Flanagan, 2010; Berger, 2010; Drulovic, 2011).  In addition to Hashimoto’s encephalopathy, voltage-gated potassium channel complex antibody-associated encephalopathy (Tan, 2008), and Morvan syndrome (progressive encephaloencephalopathy with rigidity and myoclonus) have been included as autoimmune encephalopathies. IVIG for Hashimoto’s encephalopathy was not been reviewed or commented on by the American Academy of Allergy & Immunology expert panel (2006); the European Federation of Neurological Sciences expert panel (2006); the Canadian expert panel on IVIG for neurological diseases (2007); the Gold, Stangel, and Delakas review of IVIG for neurological diseases (2007); the American Academy of Neurology & Electrodiagnostic Medicine expert panel (2009); or the AHFS or Clinical Pharmacology Online drug compendia (2011).  Because of the rarity of this disorder, it is unlikely that prospective trials will be performed.  A case series of 72 patients (Flanagan, 2010), reported from the Mayo Clinic showed improvement with glucocorticoids, but relapsed after discontinuation.  Some patients responded only to IVIG or received IVIG after failing corticosteroids.  Because of the rarity of this disorder, it is unlikely that prospective trials will be performed.
 
AUTOIMMUNE URTICARIA (ANGIOEDEMA)
There are rare case reports and two case series (Pereira, 2007; Mitzel-Kaoukhov, 2010) which describe IVIG treatment for autoimmune urticaria.  Neither the AHFS nor the Clinical Pharmacology Online drug compendia recommend IVIG for treatment of autoimmune urticaria.  No major medical group recommends IVIG for autoimmune angioedema.  The American Academy of Allergy & Immunology expert panel states, “Because there is not clear evidence that the use of IVIG benefits patients with chronic urticaria, additional studies are needed” (Orange, 2006).  
 
CARDIOMYOPATHY, DILATED CARDIOMYOPATHY
The Intervention in Myocarditis and Acute Cardiomyopathy trial, a multi-center, placebo-controlled trial to determine whether IVIG improves left ventricular ejection fraction in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis was reported in 2001 (McNamara, 2001).  This trial was done because of reports from uncontrolled studies which purported to show benefit.  The study failed to demonstrate evidence of therapeutic efficacy.   
 
CHRONIC FATIGUE SYNDROME
A randomized, double-blind, placebo-controlled trial of 3 different doses of IVIG in 99 adult patients with chronic fatigue syndrome was reported in 1999 (Volmer-Conna, 1997).  Outcome was assessed by changes in a series of self-reported measures (quality of life, standardized diaries of daily activities, profile of mood states, and Karnofsky performance scale).  No dose of IVIG was associated with a specific therapeutic benefit.  The American Academy of Allergy and Immunology recommends against the use of IVIG for chronic fatigue syndrome (Orange, 2008).
 
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
A double-blind placebo-controlled study comparing IVIg to placebo in patients with progressive or relapsing CIDP reported a significant effect of IVIg in 63% of patients compared to no effect in the placebo group.  A randomized single-blinded study comparing IVIg to plasma exchange reported equivalent beneficial outcomes for both therapies. Open-label treatment of 26 patients with type 2 diabetes and meeting electrophysiologic criteria for CIDP showed significant improvement in 21, suggesting benefit in diabetic CIDP as well. A possible advantage to IVIg treatment is the ability to administer the drug in the home.
 
A multicenter randomized, placebo-controlled trial with a 10% caprylate-chromatography purified intravenous immune globulin product given every 3 weeks for up to 24 weeks showed improvement in inflammatory neuropathy cause and treatment criteria (INCAT) in 54% of treated patients compared to 21% of placebo that was maintained through 24 week 24.   During an extension period of the trial, participants who continued to receive IVIG-C had a longer time to relapse than did patients treated with placebo (Hughes, 2008).
 
CLOSTRIDIUM DIFFICILE ENTEROCOLITIS
IVIG has been reported in single case reports and small case series to be beneficial for treatment of patients with enterocolitis unresponsive to vancomycin and metronidazole (Leung, 1991; Salcedo, 1997; McPherson, 2006; Murphy, 2006), and has been ineffective in other studies (Leung, 2007). The American Academy of Allergy & Immunology expert panel concluded that IVIG “might be beneficial” (Orange 2006).  The Medical Letter recommends IVIG for treatment of frequent relapse of C. difficile enterocolitis, based on the McPherson paper (Med Letter Drugs Ther, 2006a).  A 2008 review concluded, “Despite multiple case reports of successful treatment with IVIG, good sound clinical trials are lacking and thus make it difficult to recommend this for treatment of CDI at this time (Hedge, 2008).
 
Dermatomyositis
A randomized controlled trial comparing IVIg to placebo in 15 patients with refractory dermatomyositis reported significant increases in muscle strength in the IVIg group.  Repeated transfusions every 6 to 8 weeks may be required to maintain a benefit. (Delakas, 1993)  In 2 case series of 18 and 19 patients, a significant number of patients had reduction in corticosteroid use or were otherwise considered responders. In a non-randomized comparison of prednisone plus cyclosporine A, with or without IVIg, patients (12 with DM, 8 with PM) given IVIg had a higher probability of remission. Thus, the available data suggest benefit in DM, but are insufficient for firm conclusions. A recent patient series of IVIg in patients with refractory PM showed significant clinical improvement in more than two-thirds of patients.  IVIG for treatment of refractory dermatomyositis is recommended by the AHFS and Clinical Pharmacology Online drug compendia, and by multiple expert panels.
 
DIABETES MELLITUS, AUTOIMMUNE
A major cause of type I diabetes mellitus is considered to be autoimmune disease which destroys the insulin producing islet cells of the pancreas.  IVIG was studied in a randomized, placebo-controlled trial and found to have no benefit (Colagiuri, 1996).  The American Diabetes Association does not recommend IVIG to treat type I or type II diabetes mellitus.  Neither the AHFS nor the Clinical Pharmacology Online drug compendia recommend IVIG to treat autoimmune diabetes mellitus.
 
DIABETIC AMYOTROPHY
There are a few case reports of IVIG for amyotrophy, but no trials have been reported.  Monotherapy with IVIG was given to a total of 17 patients from 3 studies; all were considered to have improved. (Krendel, 1995; Pascoe, 1997; Jaradeh, 1999).  A randomized controlled trial (NCT00004407) was scheduled by the Mayo Clinic, but has not recruited participants.  The Canadian IVIG Hematology & Neurology Expert Panels recommends against the use of IVIG in diabetic polyneuropathy, mononeuropathy, or proximal lower limb neuropathy (Robinson, 2007).  A 2009 Cochrane review of immunotherapy for diabetic amyotrophy (Chan, 2009) concluded, “there is presently no evidence from randomized trials to support any recommendation on the use of any immunotherapy treatment in diabetic amyotrophy.”
 
DI GEORGE SYNDROME
Di George syndrome is primarily a congenital T-cell deficiency associated with defective development of organs dependent on cells of embryonic neural crest origin, and includes congenital cardiac defects, failure of parathyroid development, and absence of the thymus.  Facial abnormalities also may occur.  Serum immunoglobulin concentrations are frequently normal, but impaired antibody responses to polysaccharide and other antigens have been found in approximately one third of patients with Di George syndrome, but they seldom warrant IgG administration (Kobrynski, 2006).  
 
ENCEPHALITIS, ACUTE, DISSEMINATED
Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the CNS, commonly preceded by an infection, and predominately affects the white matter of the brain and spinal cord. It occurs predominately in pediatric patients, but can occur in adults.  It is classically described as monophasic, but can be recurrent and multiphasic, with wide variation of severity.  There is no standard therapy; most treatment approaches have employed some form of nonspecific immunosuppressant therapy including steroids, IVIG (Kleiman, 1995, Nishikawa, 1999; Sahlas, 2000; Marchioni, 2002; Ravaglia, 2006), or plasmapheresis.  No randomized controlled trials have been performed, and there have been no studies which have compared IVIG with steroids, plasmapheresis, or other immunomodulatory treatments.  The American Academy of Allergy & Immunology (Orange, 2006), the International Pediatric MS Study Group (Tenembaum, 2007), and the Canadian IVIG Hematology & Neurology Expert Panels (Robinson, 2007) recommend IVIG if corticosteroids are ineffective.
 
FISHER SYNDROME
Fisher syndrome is a rare, acute neurological disorder characterized by a triad of clinical manifestations that includes brain-damage associated abnormal coordination (ataxia), a condition that involves the paralysis of the eyes called ophthalmoplegia, and a generalized absence of reflexes (areflexia).  A Cochrane Neuromuscular Review in 2007 identified no randomized prospective controlled trials of immunotherapy in Fisher syndrome (Overall JR, 2007).  Several case reports and case series have been published on the treatment of Fisher syndrome with IVIG, and patients who received IVIG experienced clinical recovery in a slightly shorter time frame than would be expected based on the natural history of the disease (Arakawa, 1993; Zitko, 1994; Benito-Leon, 1996; Bushra, 2000; Kaushik, 2005; Mori, 2007).  Neither AHFS nor Clinical Pharmacology Online recommends IVIG for Fisher’s syndrome.  The AANEM states, “On the basis of the single retrospective analysis and case reports, it is difficult to clearly define the role of VIG in treating Fisher syndrome.  The literature suggests that best medical management may suffice for many patients (Donofrio, 2009).
 
GOOD SYNDROME (Durable Hypogammaglobulinemia Associated with Thymoma)
Good syndrome is characterized by hypogammaglobulinemia and acquired immunodeficiency associated with benign or malignant thymoma (Good, 1954).  Autoimmunity to to B lymphocyte lineage causes severe deficiency in B lymphocytes and hypogammaglobulinemia, resulting in acquired immunodeficiency vulnerable especially to bacterial infection (Kelleher, 2003).  Hypogammaglobulinemia and susceptibility to infection may persist for several years after resection of the thymoma (Tarr, 2001; Kitamura, 2009).  IVIG replacement is recommended by the International Union of Immunological Societies (IUIS Scientific Committee, 1999)
 
Guillain-Barre Syndrome
Two randomized studies comparing IVIg with plasma exchange reported equivalent outcomes for the two treatment approaches. In addition, one study has reported that there is no health benefit in combining plasma exchange with IVIg. Therefore, choice of therapy may be dictated by practical concerns, i.e., access to plasma exchange and need for hospitalization.
 
HEMOLYTIC DISEASE OF NEWBORN WITH JAUNDICE (ISO-IMMUNE HEMOLYTIC DISEASE OF NEWBORN)
A Cochrane review of 3 randomized controlled trials totalling 189 infants with rhesus and ABO incompatibility concluded, “Although the results show a significant reduction in the need for exchange transfusion in those treated with IVIG, the applicability of the results is limited.  The number of studies and infants included is small and none of the 3 included studies was of high quality…Further well designed studies are needed before routine use of IVIG can be recommended for the treatment of iso immune hemolytic jaundice (Alcock, 2002).  This review was updated in 2009 with a similar conclusion: “The role of IVIG remains uncertain, particularly in hospitals that do not use early rate of rise of bilirubin as an indicator for exchange transfusion.  Since it appears safe, it may have a role in special circumstances such as parental refusal for exchange transfusion, or where appropriate blood components for exchange transfusion are unavailable.  However, routine use of IVIG for the treatment of iso immune hemolytic jaundice cannot yet be recommended (Alcock, 2009).  The American Academy of Allergy and Immunology states, “Multiple anecdotal reports demonstrate benefit from the use of IVIG in autoimmune hemolytic anemia, but the use of IVIG should be considered only when other therapeutic modalities fail.  IVIG might decrease the need for exchange transfusion in neonates with iso-immune hemolytic jaundice.  However, there are methodologic flaws with these studies, and routine use in this setting is not recommended.”  Two randomized controlled trials reported in 2011 found conflicting results: A trial of 80 infants from the Netherlands, which randomly assigned neonates with rhesus hemolytic disease for IVIG or placebo, found no reduction in the need for exchange transfusion or rates of other adverse neonatal outcomes (Smits-Wintjens, 2011).  A study from Egypt of 90 infants were randomly assigned to 3 groups: low dose IVIG (0.5gm/kg), high dose IVIG (1g/Kg), and placebo.  There was a more rapid decrease in bilirubin, the duration of phototherapy, and hospital stay (Elalfy, 2011).
 
HYPERIMMUNOGLOBULIN M SYNDROME
Hyper-IgM syndromes are a group of disorders characterized by hypogammaglobulinemia with severely impaired production of specific antibody.  Children with hyper-IgM syndrome have decreased levels of IgG and IgA and increased or normal levels of IgM.  Although B cells are present, there is an inability to generate specific antibody.  As a result, these individuals have recurrent infections similar to those of patients with agammaglobulinemia.  Regular replacement therapy with IVIG is crucial for individuals with this disorder, whether it is due to the X-linked or autosomal recessive varieties (Levy, 1997; Winkelstein, 2003; Quartier, 2004).  Hyperimmunoglobulin M is also seen in patients with Waldenstrom’s hyperglobulinemia, and rarely in B-cell lymphomas, and may be associated with low immunoglobulin G.  The American Academy of Allergy and Immunology (Orange, 2006) recommends IVIG for children with X-linked hyper-IgM syndrome and other autosomal recessive varieties (Orange, 2006).
 
INCLUSION BODY MYOSITIS
Inclusion body myositis (IBM) is a late onset inflammatory muscle disease (myopathy) with a distinctive pattern of proximal and distal limb atrophy and weakness.  In published series it has accounted for between 17 to 30% of all idiopathic inflammatory myopathies but the true proportion may be much higher.  In neuromuscular disease referral centers IBM is the commonest acquired myopathy over the age of 50 years.  Muscle biopsy is essential for diagnosis and can be pathognomonic. It usually shows varying degrees of inflammation, with muscle fibres containing rimmed vacuoles but also additional features which include the presence of nuclear and cytoplasmic inclusions and the abnormal deposition of proteins such as amyloid, ubiquitin and phosphorylated tau. There are agreed criteria for the diagnosis of IBM utilizing clinical, laboratory and biopsy findings.  In the majority of cases IBM is a sporadic and isolated disorder. However there are a few cases where IBM occurs in association with an autoimmune disease.  In rare instances familial cases of IBM have occurred but as these are usually not associated with inflammation they are called hereditary inclusion body myopathies (h-IBM) They are a heterogenous group of disorders characterized clinically by progressive muscular weakness and atrophy beginning in the hands or feet. So far, five different hereditary forms (1 autosomal recessive, 4 autosomal dominant) have been characterized. Dalakas and colleagues have reported on a double-blind, placebo-controlled crossover study comparing IVIg to placebo in 19 patients with inclusion body myositis (Delakas, 1997).  There was no statistically significant improvement in overall muscle strength in the IVIg group compared to the control placebo group. (Delakas, 2001) reported a RCT of 36 patients with biopsy-proven IBM who received IVIG + prednisone versus placebo + prednisone.  IVIG combined with prednisone for a 3-month period was not effective in IBM.  A crossover study of 22 patients with sporadic IBM were treated with high-dose IVIG versus placebo (Walter, 2000).  Treatment was considered of mild benefit.  The European Federation of Neurological Sciences (Skeie, 2006); the American Academy of Allergy & Immunology (Orange, 2006); and the Canadian IVIG Hematology & Neurology Expert Panels (Robinson, 2007) recommend against the use of IVIG for treatment of inclusion body myositis.
 
IRAK4  IMMUNODEFICIENCY
Four Mendelian primary immunodeficiencies associated with impaired signaling of the Toll Like Receptor (TLR) pathway have been reported, one of which is IRAK4 (Interleukin-1 Receptor Associated Kinase 4).  Autosomal recessive IRAK-4 deficiency was first discovered in 2003 (Picard, 2003) and has been described in a less than 100 patients as of 2011.  Patients with IRAK-4 deficiency present with invasive and non-invasive pyogenic bacterial infections, but have normal resistance to common fungi, parasites, viruses, and many bacteria.  Clinical status andoutcome improve with age thought to be due to the development of adaptrive antigen-specific T- and B-lymphocyte responses.  IVIG is recommended empirically until the patient is at least 10 years old (Picard, 2011).  IVIG for IRAK4 immunodeficiency meets coverage criteria based on Expert Opinion, as the number of cases would not allow for appropriate treatment trials, and case studies to date indicate benefit .
 
Kawasaki Syndrome and Other Vasculitides
Randomized, multicenter studies have shown that high-dose IVIg plus aspirin, given within the first 10 days after the onset of fever, is safe and effective in reducing the prevalence of coronary artery abnormalities in Kawasaki Syndrome.
 
A RCT of single course IVIg (n=17) vs. placebo (n=17) in patients with persistent active Wegener’s granulomatosis or microscopic polyangiitis associated with anti-neutrophil cytoplasmic antibody found significantly more responders in the IVIg treatment group at 3 months, but no significant differences after 3 months or in the frequency of relapse or use of other medications.  Data are inadequate regarding the effectiveness of IVIg in other vasculitides including polyarteritis nodosa and rheumatoid arthritis.
 
MULTIFOCAL MOTOR NEUROPATHY
In 2010, the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society published guidelines on the management of multifocal motor neuropathy (MMN). The guideline recommends the use of IVIg in the initial and maintenance treatment in patients with MMN (Joint Task Force of the EFNS and the PNS, 2010). Four randomized, controlled, double-blind trials of IVIg for treating MMN (Azulay et al., 1994; Van den Berg et al., 1995; Federico et al., 2000; Le´ ger et al., 2001) have been summarized in a Cochrane systematic review (van Schaik et al., 2005). IVIg treatment was superior to placebo in inducing an improvement in muscle strength in patients with MMN.
 
Multiple Myeloma
A review of the current literature shows several review and meta-analysis articles but no reports of trials using IVIG for myeloma patients before or after stem cell transplant.
 
Blade and Rosifiol (2007) stated the highest risk of infection in myeloma patients is within the first two months of initiation of therapy and in patients with relapsed and refractory disease.  The increased susceptibility to infections is multifactorial with the major cause being the impaired antibody production leading to a decrease in uninvolved immunoglobulins.  There has been controversy about infection prophylaxis in patients with MM but high-dose immunoglobulins are not recommended.
 
Raanani (2009) also noted in his meta-analysis that causes for infections in patients who receive HSCT are multifactorial and consist also of causes other than hypogammaglobulinemia.  The authors concluded there was no advantage to the use of IVIG in terms of survival or infection prevention.
 
Other authors have also recommended the limited use of IVIG for myeloma patients: Nucci (2009): consider IVIG if serum IgG level < 500 mg/dL and recurrent serious infection despite prophylactic antibiotics.  Ludwig (2007): prophylactic measures such as long-term antibiotic or antiviral medication or use of intravenous immunoglobulins is recommended in patients with repeated infectious complications.
 
Multiple Sclerosis
In terms of its impact on the acute exacerbation rate in patients with relapsing-remitting MS, IVIg is comparable to treatment with beta interferon. Despite a reduction in the acute exacerbation rate, data are inconclusive regarding the impact of IVIg on patients’ disability. There are insufficient data to evaluate the effectiveness of IVIg in treating patients with chronic progressive MS.
 
A high-quality RCT compared IVIg to placebo in 67 patients, the majority of whom had chronic progressive disease; the trial was terminated early due to lack of benefit either in patients who remained clinically stable or in those with evidence of disease activity. Small series data also suggest no benefit.
 
In 2002 the American Academy of Neurology published a technology assessment on therapies for multiple sclerosis.  This assessment provided a rating of the recommendations, including A (established as effective), B (probably effective, ineffective, or harmful), C (possibly effective, ineffective or harmful) or U (data inadequate). This assessment offered the following recommendation regarding IVIg:  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 relapsing-remitting multiple sclerosis. (Type C recommendation)
 
The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression. (Type C recommendation). In contrast, the American Academy of Neurology recommended the use of interferon beta (Type B recommendation) and glatiramer acetate (Type A recommendation). This assessment suggests that IVIg is no longer considered a drug of choice for relapsing-remitting MS, and thus the policy statement in this policy has been revised to indicate that IVIg is not medically necessary. A literature search for the period of 2002 to December 2004 did not identify any additional randomized trials that would prompt reconsideration of the conclusions of the American Academy of Neurology assessment.
 
Myasthenia Gravis
One RCT (total n=87) and one retrospective chart review (total n=54)  compared IVIg treatment to plasma exchange in acute myasthenic crisis. Myasthenic crisis was defined as an acute episode of respiratory muscle weakness, defined by an forced vital capacity (FVC) of <=1.0 liter or negative inspiratory force of <= 20 cm H20, or requirement of mechanical ventilation. One crossover study compared these therapies in 12 patients with moderate-to-severe disease in a stable phase. Results for all 3 trials showed that IVIg and plasma exchange had similar efficacy over time, although improvement may be more rapid with plasma exchange. Series data support benefit with IVIg treatment in patients with acute exacerbations and with refractory disease or who are unable to tolerate standard treatment. One series of 10 children with refractory disease suggests short-term benefit with IVIg but limited long-term benefit.  Refractory myasthenia gravis has been defined as those patients with persistent symptoms despite immunosuppressive treatment with prednisone and/or azathioprine or those unable to tolerate steroid therapy.
 
Feasby et al.: Given the limited evidence available, the expert panel agreed IVIG should not be used as maintenance therapy for chronic myasthenia gravis.
 
Skeie et al.: Trials have not shown evidence of improved functional outcome or steroid-sparing effect with repeated use of IVIG in moderate or severe stable MG (class I evidence).
 
MYD88 gene deficiency
Four Mendelian primary immunodeficiencies associated with impaired signaling of the Toll Like Receptor (TLR) pathway have been reported, one of which is autosomal recessive MyD88 deficiency which was first discovered in 2008. (von Bernuth, 2008).  Deficiency in the MYD88 gene results in invasive pyogenic infections.  IVIG is not recommended for patients with MYD88 gene deficiency by any review group, and is not recommended in the review of this deficiency by Picard, et al (Picard, 2011).
 
NEONATAL SEPSIS
A 2010 Cochrane review found no benefit, but recommended waiting on the International Neonatal Immunotherapy Study results before a definitive conclusion was reached.  The INIS Collaborative Group randomized controlled trial was reported in September 2011 (Brocklehurst, 2011) and found no benefit of IVIG in infants with neonatal sepsis.
 
PARANEOPLASTIC RETINOPATHY (CANCER ASSOCIATED RETINOPATHY, MELANOMA ASSOCIATED RETINOPATHY, AUTOIMMUNE RETINOPATHY ASSOCIATED WITH NEOPLASM) Paraneoplastic vision loss is characterized by sudden, progressive loss of vision associated with photosensitivity, ring scotomata, visual field defects, and abnormal electroretinogram believed to be caused by an autoimmune effect on the retina or optic nerve from anti-retinal autoantibodies associated with a remote cancer (Jacobson, 1990; Guy, 1999; Katsuta, 2002).  Autoantibodies (anti-recoverin, anti-enolase, anti-carbonic anhydrase II, and anti-transducin) affect both rod and/or cone function, causing rapid visual loss (Murphy, 1997; Adamus, 2004; Dot, 2005; Weleber, 2005; Adamus, 2009).  No clinical trials have been published on the use of IVIG for treatment of paraneoplastic vision loss, cancer associated retinopathy, or melanoma associated retinopathy.  No published paper from any IVIG expert panel has reviewed IVIG for treatment of paraneoplastic vision loss.  A few case reports suggest improvement following IVIG for paraneoplastic vision loss (Guy,1999; Keltner, 2001; Subhadra, 2008), and reduction in anti-enolase antibody has been described following IVIG (Adamus (2004).  Neither AHFS nor Clinical Pharmacology Online drug compendia recommend IVIG for treatment of paraneoplastic retinopathy.  IVIG for paraneoplastic retinopathy is considered to meet Primary Coverage Criteria because 1) of the critical nature of this disorder; 2) of the lack of other appropriate therapeutic measures; 3) it is unlikely that prospective trials will be performed due to the rarity of this condition; and 4) there are published case series indicating benefit.  
 
Paraneoplastic Syndrome (Eaton-Lambert Disease)
Results of a double-blind, placebo-controlled, crossover, randomized study of IVIg versus placebo in 11 patients with paraproteinemic IgM demyelinating polyneuropathy showed only a mild and transitory effect in 3 patients.  There are inadequate data on the use of IVIg in paraneoplastic syndromes, such as Eaton-Lambert disease.  
 
PEMPHIGUS AND OTHER AUTOIMMUNE BLISTERING DISEASES
Corticosteroids and immunosuppressive agents are considered first line therapy. IVIG has been shown to decrease circulating autoantibodies in pemphigus, and addition of immunosuppressive drugs to IVIG has an additive effect.  Based on uncontrolled studies (Ahmed, 2003), IVIG therapy is the preferred therapy for patients who are resistant, nonresponsive, have contraindications, or develop serious catastrophic adverse effects.  No clinical trials have been reported for IVIG for pemphigus or other autoimmune blistering diseases.  Two randomized controlled trials are listed on clinicaltrial.gov.  NCT00483119 is an ongoing FDA sponsored trial at NYU Medical Center, initiated in 2007 with estimated completion date of 2011, comparing IVIG versus IVIG plus cyclophosphamide in patients with pemphigus that are not responding to, or have developed complications from, standard therapy.  A second study, in Japan (NCT00809822) recently completed but unreported, is a randomized, placebo controlled trial of IVIG for patients with bullous pemphigoid unresponsive to corticosteroids.   Prospective, non-randomized, open label clinical studies on patients who are unresponsive to corticosteroids and immunosuppressive agents have shown response to IVIG (Toth, 1999; Engineer, 2000; Ahmed, 2001; Sami, 2002; Bystryn, 2002; Ahmed, 2002; Baum, 2006).  IVIG has not been compared to newer biologics (e.g., anti-tumor necrosis alfa drugs).
 
POST TRANSPLANT HYPOGAMMAGLOBULINEMIA
Hypogammaglobulinemia has been identified following lung (Kawut, 2005; Yip, 2006; Robertson, 2009), heart (Corales, 2000), AND kidney (Boddana, 2011) transplantation.  There has been consideration that this may be due to the use of mycophenolate mofetil to prevent allograft rejection, and this drug is known to be associated with an increased risk of bacterial infection.   
 
POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
PDLDs are a heterogenous group of abnormal lymphoid proliferations that occur after solid organ transplant or hematopoietic transplantation.  PTLDs range from hyperplasia to aggressive lymphomas with 60-70% being Epstein-Barr virus positive.
 
PREVENT RECURRENT PREGNANCY LOSS IN UNSELECTED POPULATION  
A Cochrane review on Immunotherapy for recurrent miscarriage published initially in 2006, and edited in 2010, looked at 20 trials on various forms of immunotherapy, including 7 with IVIG, for treatment of recurrent abortion.  They concluded that IVIG provided no significant beneficial effect over placebo in approving live birth rate (Porter, 2010).  Another systematic review of eight trials (Hutton, 2007) involving 442 women found that IVIG did not significantly increase the odds ratio of live birth when compared with placebo for treatment of primary recurrent miscarriage (primary - miscarriage occurring in women with no recognized cause, e.g, antiphospholipid syndrome).  
 
PREVENT RECURRENT PREGNANCY LOSS IN ANTIPHOSPHOLIPID SYNDROME
The Pregnancy Loss Study Group multicenter, placebo-controlled pilot study of IVIG treatment of antiphospholipid syndrome during pregnancy compared treatment with heparin and low-dose aspirin plus IVIG with heparin and low-dose aspirin plus placebo in a group of 16 women who met strict criteria for antiphospholipid syndrome in 16 women (Branch, 2000).  Obstetrical outcomes were excellent in both groups, with all women being delivered of live-born infants after 32 weeks gestation.  A second randomized controlled trial of 40 women with recurrent abortion (at least 3 occurrences) and repeatedly positive test results for anticardiolipin or lupus anticoagulant were randomized to receive IVIG or low molecular weight heparin plus low dose aspirin (Triolo, 2004).  The women treated with low molecular weight heparin plus low-dose aspirin had a higher rate of live births (84%) than those treated with IVIG (57%).  A third randomized controlled trial (Dendrinos, 2009) randomly allocated 85 women to receive low molecular weight heparin plus low-dose aspirin or IVIG.  Low molecular weight heparin plus low-dose aspirin (72.5%) resulted in a significantly higher live birth rate than IVIG (39.5%) in treatment of antiphospholipid antibody syndrome in women with recurrent abortion.  The American Academy of Allergy, Asthma, and Immunology recommends against use of IVIG to prevent pregnancy loss in women with antiphospholipid syndrome (Orange, 2006).
 
PURE RED CELL APLASIA (PRCA)
Pure red-cell aplasia is defined as the absence of mature erythroid precursors in a bone marrow that otherwise exhibits normal cellularity.  Acquired pure red-cell aplasia may occur in association with neoplasms (such as lymphoproliferative disorders), thymoma, autoimmune disorders, pregnancy, or as a consequence of chronic human parvovirus B19 infection in an immunologically incompetent host.  PRCA may also develop after exposure to drugs (erythropoietin or tacrolimus).  
 
There are case reports of effectiveness of IVIG in these conditions, and also in patients with HIV.  The Canadian Hematological Expert Panel recommends IVIG for pure red blood cell aplasia if the PRCA is refractory to standard therapy.
 
RHEUMATIC FEVER, ACUTE
A randomized placebo-controlled trial in 59 patients with rheumatic fever who were treated with either IVIG or placebo revealed that IVIG treatment did not reduce the valvulitis or altered the natural history of the disease (Voss, 2001). A Cochrane Review concludes that IVIG is not indicated in treatment of acute rheumatic fever (Cillers, 2003).
 
STAPHYLOCOCCAL TOXIC SHOCK SYNDROME
According to the Drug Compendia, the American College of Pediatrics suggests that IGIV may be considered in the management of severe staphylococcal toxic shock syndrome when the infection is refractory to several hours of aggressive therapy, an undrainable focus is present, or the patient has persistent oliguria with pulmonary edema.  The American Academy of Allergy, Asthma, and Immunology lists IVIG as “probably beneficial” in staphylococcal toxic shock (Orange, 2006) although they provide no references.  A review of therapeutic uses of immunoglobulins in pediatrics (Stiehm, 2010) lists IVIG as probably beneficial, and references from two textbooks (Pickering, 2009; Feigen, 2009), support this use.
 
STEVENS-JOHNSON SYNDROME
Stevens-Johnson syndrome is a potentially fatal disorder.  A prospective non-comparative study of IVIG showed no benefit on mortality or progression (Bachot, 2003).   The American Academy of Allergy, Asthma, and Immunology recommends IVIG as “probably beneficial” for treatment of Stevens-Johnson syndrome (Orange, 2006), although the reference given in support of that decision (Trent, 2003) addresses toxic epidermal necrolysis only.  The Medical Letter (2006b) states that there is no clear evidence of benefit for Stevens Johnson syndrome, “but [it is]thought to be potentially life-saving.  Gurcan and Ahmed in their review of IVIG state, “The current viewpoint is that IVIG may be effective in Stevens-Johnson syndrome and toxic epidermal necrolysis if used very early (within 48 h of onset of clinical features) and at high doses for 3-5 days consecutively (Gurcan, 2007).  
 
THROMBOCYTOPENIA, NEONATAL ALLOIMMUNE
IVIG, to prevent severe intra-uterine thrombocytopenia, given to an expectant mother who had previously delivered an infant with neonatal alloimmune thrombocytopenia, was initially described in a prospective case series of 7 women  (Bussel, 1988).  Since that time there have been a number of case series and prospective single arm or comparative drug trials of IVIG (Bussel, 1996; Berkowitz, 2006; Berkowitz, 2007), but there have been no randomized controlled trials (RCTs) comparing IVIG to no therapy (Rayment, 2005; Bassler, 2008).
 
The American Academy of Allergy and Immunology states, “there are anecdotal data supporting the use of IVIG for antenatal therapy of fetomaternal alloimmune thrombocytopenia.  Although there are no randomized trials to support this practice, use of IVIG has become routine first-line therapy in this setting.” (Orange, 2006).  A Cochrane review of IVIG for antenatal interventions for fetomaternal alloimmune thrombocytopenia concluded, “There are insufficient data from randomized controlled trials to determine the optimal antenatal management of fetomaternal alloimmune thrombocytopenia” (Rayment, 2005).  The American College of Obstetrics and Gynecology published a state of the art paper in 2006 stating this therapy is the treatment of choice (Berkowitz, 2006).  In a review of neonatal alloimmune thrombocytopenia, (Vinograd, 2010), the authors concluded, “[N]oninvasive approaches and the implementation of risk stratification (including combination therapy of IVIG with steroids and/or the use of more than 1gm/kg/week of IVIG) are appropriate in the management of fetal alloimmune thrombocytopenia.  Neither the AHFS nor the Clinical Pharmacology Online compendia have position statements on this therapy.  A RCT of antenatal IVIG given in either 2gm/kg/wk or 1gm/kg/wk plus prednisone starting at approximately 20 weeks of gestation, in women with very high risk, high risk and standard risk for neonatal alloimmune thrombocytopenia was initiated in 2001 (expected completion date Feb 2012) at Weill Medical College of Cornell University (NCT00194987), but results of the full study are not yet available.  The subset of 73 women in the standard risk group (defined as women with documented alloimmune thrombocytopenia who had not delivered an infant with an intracranial hemorrhage in a prior pregnancy) showed “excellent” outcomes inb both groups (Berkowitz, 2007).
 
TRANSPLANTATION, ANTIBODY MEDIATED REJECTION
One RCT of 30 patients published in 2001 suggested that IVIg is at least as good as anti-CD3 in combating corticosteroid-resistant rejection of kidney transplants (Casadei, 2001). Later, in 2003-4, findings from the NIH IG02, a double-blind placebo-controlled trial, were published (Jordan, 2003).  The trial randomized 101 highly sensitized renal transplant candidates to receive either 4 monthly infusions of IVIg or placebo prior to transplant. If transplanted, additional infusions were given monthly for 4 months. IVIg significantly reduced PRA levels in study subjects compared to placebo, resulting in a higher transplant rate. For example, a total of 24 patients subsequently underwent transplant, 16 in the IVIg group and 8 in the placebo group. There was acceptable graft survival in both groups. Desensitization protocols varied among transplant centers; certain protocols commonly used are referred to as the Cedars-Sinai protocol and the Johns Hopkins protocol. The Cedars-Sinai protocol consisted of high-dose IVIg (2 g/kg) and was offered to patients awaiting either a deceased or live donor (Jordan, 2003). The Johns Hopkins protocol consisted of low-dose IVIg (100 mg/kg) in combination with plasmapheresis with or without treatment with anti-CD-20 (i.e., Rituxan) (Montgomery, 2004).
 
A retrospective cohort study published in 2009 compared outcomes in pediatric liver transplant patients entered into a multicenter Registry who did (n=336) and did not (n=1,612) receive IVIg within 7 days of transplantation (Bucuvalas, 2009). The investigators assumed that IVIg given within this timeframe was used for prophylaxis of antibody mediated rejection (AMR), rather than for treatment. The Kaplan-Meier probability of patient survival was not significantly different between groups (hazard ratio [HR]: 0.97, 95% CI: 0.71-1.39). However, the risk of graft rejection was significantly lower in patients treated with immunoglobulin. In the first 3 months after transplant, 31% of patients who received immunoglobulin and 40% of those not treated had an episode of graft rejection (p=0.02). Similarly, the proportion of patients with 2 or more episodes of graft rejection was significantly lower among those who received immunoglobulin (13.1%) than those who did not (19.2%), p=0.009. Patients were not randomized to treatment group, and there may have been differences in those treated or not treated with immunoglobulin that affected outcomes.
 
A variety of protocols also have been developed for the treatment of AMR, often in combination with other therapies, such as plasmapheresis or anti-CD-20 (Casadei, 2001; Ibernon, 2005; Jordan, 2005; Lehrich, 2005). The majority of studies of IVIg in the transplant setting are retrospective case series from single institutions. Therefore, it is not possible to compare immunomodulatory regimens to determine their relative efficacy. Nevertheless, in part based on the large volume of literature published on this subject, it appears that IVIg is a component of the standard of care for the management of AMR.
  
VON WILLEBRAND’S DISEASE, ACQUIRED  
The Canadian IVIG Hematology Expert Panel does not recommend IVIG for routine use in the treatment of acquired Von Willebrand’s disease, but states “IVIG may be considered one option among adjunctive therapies in the treatment of acquired von Willebrand’s disease in urgent situations (e.g., active bleeding or preoperatively) (Robinson, 2007).  No other major medical society has published recommendations on the use of IVIG in von Willebrand’s disease.  Neither the AHFS nor Clinical Pharmacology Online recommend coverage of IVIG for von Willebrand’s disease (2011).
 
WEST NILE VIRUS FEVER
The West Nile virus has become endemic in the U.S. since 1999 (Lanciotti, 1999), has been found in mosquitoes, birds, horses, and other animals (Rappole, 2000; Campbell, 2002), and antibodies against West Nile virus have become much more common in the plasma of blood donors.  Reports have been published of transmission of the disease following solid organ transplantation (Iwamoto, 2003; Rhee 2011).  There is no specific treatment for West Nile virus infection, and in most cases the disease is self-limited and treated with supportive care (although some have predicted long-term neurological deficit (Sejvar, 2007).  But in persons who are immunosuppressed, or who are elderly, are at risk of fatal meningoencephalitis.  There are single and multi-case reports of use of IVIG with high specific antibody titers against West Nile virus with apparent clinical improvement (Shimoni, 2001; Hamdan, 2002; Haley, 2003; Makhoul, 2009; Saqueib, 2008; Rhee, 2011).  IVIG is recommended for treatment of confirmed West Nile encephalomyelitis by Clinical Pharmacology Online (2012).
 
2013 Update
There is no new literature to support changes in the coverage statement with the exception of multifocal motor neuropathy (MMN).
 
A consensus statement addressing IVIG for treatment of neuromuscular conditions was written by Donofrio et al. (2009) writing for the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).  They noted that in small studies improvement with IVIG was noted only in patients with conduction block on nerve conduction studies.  
 
This article also referenced dosing recommendations from the European Federation of Neurological Societies, Elovaara I, et al., 2008 (http://www.efns.org/Guideline-Archive-by-topic.389.0.html) who recommend:
 
    • IVIG (2g/kg in 2-5 days) as first-line treatment (level A1)
    • (If the initial IVIG treatment is effective, repeated infusions should be considered (level C2)
 
Attempts should be made to decrease the dose to discover whether a patient still needs IVIG. The frequency of maintenance therapy should be guided by the individual response, whereby typical treatment regimens are 1 g/kg every 2-4 weeks or 2 g/kg every 4-8 weeks.
 
A Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society published guidelines in 2010.  This article goes into great detail about the diagnostic and clinical criteria for MMN.  IVIG recommendations are very similar to those published in 2008.
 
1. IVIg (2 g/kg given over 2–5 days) should be the first line treatment (level A) when disability is sufficiently severe to warrant treatment.
2. Corticosteroids are not recommended.
3. If the initial treatment with IVIg is effective, repeated IVIg treatment should be considered in selected patients (level C). Typical treatment regimens are 1 g/kg every 2–4 weeks or 2 g/kg every 1–2 months.
4. If IVIg is not sufficiently effective then immunosuppressive treatment may be considered. However,
no agent has shown to be beneficial in a clinical trial and data from case series are conflicting.
 
This statement is made in AAN guidelines, Patwa et al., 2012:
IVIg is probably effective and should be considered for treating moderate to severe myasthenia gravis
and multifocal motor neuropathy (Level B).  However the authors did note the lack of available data to address optimal treatment dosing, interval, and duration.
 
Rippling Muscle Disease
This is one of several related diseases, also called Caveolinopathies, usually associated with a Caveolin-3 deficiency. This disease may also be related to an autoimmune process. There is very little literature addressing treatment of this disorder. GeneReviews addresses treatment of manifestations with aggressive supportive care but does not mention systemic therapy (Bruno, 2012). There are reports of successful treatment with plasma exchange, steroids and azathioprine in 2 patients who also have myasthenia gravis (Schoser, 2009) and in 2 patients with azathioprine alone (Muller-Feler,1999).
  
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Hemolytic Disease of the Fetus and Newborn
Hemolytic disease of the fetus and newborn (HDFN), also called erythoblastosis fetalis, is caused by maternal antibodies that pass though the placenta and attack fetal red blood cells. The disease presents with anemia and hydrops (edema) in fetuses, and with anemia and jaundice in newborns. Common treatment options are phototherapy and exchange transfusion (ET). IVIg is proposed as a less invasive alternative to ET.
 
In 2014, Louis et al published a systematic review and meta-analysis of studies on IVIg for treatment of HDFN (Louis, 2014). The authors identified 12 RCTs, which they assessed using the Cochrane risk of bias tool; 3 trials were judged to have low risk of bias, and 9 had high risk of bias. All trials reported adequate sequence generation for randomization, but only 3 reported details about allocation concealment, and only 3 reported details of blinding. The primary outcome of interest was need for ET. In the 3 studies with low risk of bias, a meta-analysis found no significant difference in the need for ET with IVIg or a control intervention (RR=0.82; 95% CI, 0.53 to 1.26). However, a meta-analysis of 6 studies considered to be at high risk of bias found significantly greater reductions in the need for ET with IVIg (RR=0.23; 95% CI, 0.13 to 0.40). The authors also presented analyses separately for studies of neonates with Rh isoimmunization (n=9 trials, 426 neonates) and those with ABO isoimmunization (n=5 trials, 350 neonates). IVIg significantly reduced the need for ET in these stratified analyses, but most of the studies in the Rh isoimmunization analysis and all studies in the ABO isoimmunization analysis were judged to have high risk of bias.
 
Previously, in 2002, a Cochrane review identified 3 RCTs with a total of 189 infants on IVIg for iso immune hemolytic jaundice in newborns (Alcock, 2002). All 3 studies, published in the 1990s compared a single dose of IVIg in combination with phototherapy to phototherapy alone. Meta-analysis found that the need for ET was significantly lower in the group receiving IVIg than the control group (pooled RR=0.28; 95% CI, 0.17 to 0.47). Moreover, the mean number of ETs per neonate was significantly lower in the IVIg group (WMD = -0.52; 95% CI, -0.70 to -0.35). No adverse reactions were reported in the IVIg group, but 3 infants in the control group had adverse reactions (there was 1 case each of hypoglycemia, hypocalcemia, and sepsis).
 
Data from meta-analyses of RCTs found significant reduction in ET use in newborns with HDFN treated with IVIg. A number of studies were judged to be at high risk of bias, but this was largely due to a lack of blinding, and blinding may not be critical given the objective outcome measures.
 
Autoimmune Mucocutaneous Blistering Diseases
Several systematic reviews focused on IVIg for toxic epidermal necrosis (TEN) and/or Stevens-Johnson syndrome (SJS). Most recently, in 2015, Barron and colleagues identified 13 studies of patients who met diagnostic criteria for TEN or SJS and received IVIg alone or in combination with other medications (Barron, 2015). Eight studies included a control group, but none were RCTs. All control patients received corticosteroids and in 4 of the studies, patients in the IVIg group received concomitant corticosteroid therapy. A meta-analysis of all included studies did not find a statistically significant benefit of IVIg therapy for mortality (standardized mortality ratio [SMR], -0.32; 95% CI, -0.77 to 0.12). Logistic regression analyses found that there were reductions in SMR as dosage of IVIg increased. A sensitivity analysis with the 2 studies that used the lowest doses of IVIg excluded found a statistically significant reduction in SMR in IVIg-treated groups (SMR=0.70; 95% CI, 0.51 to 0.96).
 
Systemic Lupus Erythematosus
A 2014 systematic review by Sakthisweary and colleagues identified 13 studies on IVIg for treatment of SLE.75 Three studies had control groups, and only 1 was an RCT (Sakthisweary, 2014). Most studies had small sample sizes; only 3 had more than 50 patients, and the single RCT included only 14 patients. In a meta-analysis of 6 studies (total of 216 participants), there was a statistically significant difference in SLE disease activity in IVIg-treated groups (SMD=0.58; 95% CI, 0.22 to 0.95). This analysis is limited because there were few data in non-IVIg treated patients. A meta-analysis of data from 8 studies on the effect of IVIg on complement levels found a pooled response rate of 30.9% (95% CI, 22.1 to 41.3). Findings on other outcomes were not pooled. Due to the limited amount of data from controlled studies, evidence on IVIg for SLE is insufficient to draw conclusions on health outcomes.
 
Treatment of Neonatal Sepsis
A 2015 Cochrane review identified 9 trials that compared IVIg with placebo or no intervention in neonates (<28 days old) with suspected or proven infection (Oohlsson, 2015). Studies included a total of 3973 infants; the largest trial had a sample size of 3493 and contributed 90% of the data. Meta-analysis of all 9 trials found no statistically significant difference in mortality rate with IVIg versus control (RR=0.95; 95% CI, 0.80 to 1.13). Meta-analysis of 3 trials found that IVIg significantly reduced the length of the hospital stay compared with a control intervention (mean difference, -4.08; 95% CI, -6.47 to -1.69). Results were not pooled for other outcomes.
 
Postpolio Syndrome
In 2015, Huang et al published a systematic review and meta-analysis of RCTs and nonrandomized prospective studies on IVIG for treatment of postpolio syndrome (Huang, 2015). The authors identified 3 RCTs with a total of 241 patients and 5 prospective studies with 267 patients. The primary outcomes of interest were severity of pain, fatigue, and change in muscle strength 2 to 3 months after IVIg administration. Metaanalyses of RCT data found no statistically significant differences between IVIg and placebo-treated groups on any of these outcomes. For example, the pooled mean difference in pain scores (0 to 10 [visual analog scale]) from the 3 RCTs was -1.02 (95% CI, -2.51 to 0.47). Meta-analysis of the 2 RCTs that reported change in fatigue scores found a WMD of 0.28 (95% CI, -1.56 to 1.12). The small number of RCTs and the negative findings of the Huang et al review represent insufficient evidence of efficacy of IVIg for postpolio syndrome.
  
2017 Update
A literature search conducted through January 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Toxic Shock Syndrome
It is also called as Streptococcal toxic shock syndrome. Streptococcal toxins induce the release of inflammatory cytokines which causes capillary leak and tissue damage resulting in shock, multiorgan failure and death.
 
The evidence for use of IVIG treatment for toxic shock syndrome is limited and includes one small RCT and multiple observational studies (Linner, 2014; Kaul, 1999; Norrby-Teglund, 2005; Shah, 2009). IVIG is used for treatment of septic shock syndrome to boost antibody levels via passive immunity. The RCT randomized 21 adult patients with toxic shock syndrome to IVIG or placebo (Darenberg, 2003). The mortality rates were 10 versus 36 percent, but statistical significance was not reached. In a prospective observational study, 23 patients receiving IVIG therapy were compared 44 patients who received placebo. The OR for survival was 5.6 with IVIG versus placebo (p = 0.03). Proportion of patients alive at 28 days was 87 versus 50 percent (Linner, 2014). In 2 retrospective studies, 27 patients with toxic shock syndrome treated with IVIG were compared with historical controls (Kau, 1999; Norrby-Teglund, 2005). While the mortality was lower with IVIG compared to historical controls, lack of randomization or statistical adjustment of the 2 groups pose potential difficulties in interpreting the results. A retrospective study including 192 children with toxic shock syndrome failed to show improvement in outcomes with IVIG (Shah, 2009).
 
Section Summary: Toxic Shock Syndrome
The evidence for use of IVIG treatment for toxic shock syndrome consists of a small RCT and multiple observational studies. Majority of these studies have shown beneficial effect on mortality.
 
Warm Antibody Autoimmune Hemolytic Anemia
Also known as autoimmune hemolytic anemia, it occurs commonly due to IgG antibodies that react with protein antigens on the red blood cell surface at body temperature.
 
Published literature on the use of IVIG in warm antibody autoimmune hemolytic anemia is limited to observational data of 37 patients pooled from 3 institutions (Flores, 1993), and a case report (MacIntyre, 1985). Overall, 29 of 73 patients (39.7%) responded to IVIG therapy. Because of limited therapeutic value, it is used in patient’s refractory to conventional therapy with prednisone and splenectomy or as a conjunctive therapy in patients with very severe disease. Further, the effect is usually transient unless repeated courses are given every three weeks.
 
Section Summary: Warm Antibody Autoimmune Hemolytic Anemia
The evidence for IVIG treatment of Crohn disease consists of pooled case series and a single case report.
 
Antiphospholipid Syndrome
It is an autoimmune disease that results due to development of antibody against phospholipids protein causing venous or arterial thromboses and/or pregnancy morbidity. Published literature on the use of IVIG in antiphospholipid syndrome includes a pooled analysis of 250 case reports from a registry (Bucciarelli, 2006). Results showed that a higher proportion of patients survived after the episode of antiphospholipid syndrome among patients who received triple therapy of anticoagulants, corticosteroids, plasma exchange and/or intravenous immunoglobulins compared to combinations that did not use plasma exchange, IVIG or both.
 
For individuals who are adults with toxic shock syndrome who receive IVIG therapy, the evidence includes 1 small RCT and multiple observational studies. Relevant outcomes are overall survival, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for toxic shock syndrome in adults has shown reductions in mortality in the small RCT and multiple observational studies. The evidence is sufficient to determine the effects of the technology on health outcomes.
 
For individuals who have warm antibody autoimmune hemolytic anemia and are refractory to prednisone and splenectomy, the evidence includes pooled observational data. Relevant outcomes are change in disease status, quality of life, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested potential benefit with IVIG therapy in selective patients. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have antiphospholipid syndrome, the evidence includes pooled data from a registry. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested potential mortality benefit with IVIG therapy. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
 
  
 
  

CPT/HCPCS:
90283Immune globulin (IgIV), human, for intravenous use
90284Immune globulin (SCIg), human, for use in subcutaneous infusions, 100 mg, each
J1459Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1555Injection, immune globulin (cuvitru), 100 mg
J1556Injection, immune globulin (bivigam), 500 mg
J1557Injection, immune globulin, (Gammaplex), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1559Injection, immune globulin (Hizentra), 100 mg
J1561Injection, immune globulin, (Gamunex/Gamunex-C/Gammaked), nonlyophilized (e.g., liquid), 500 mg
J1562Injection, immune globulin (Vivaglobin), 100 mg
J1566Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg
J1568Injection, immune globulin, (Octagam), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1569Injection, immune globulin, (Gammagard liquid), nonlyophilized, (e.g., liquid), 500 mg
J1572Injection, immune globulin, (Flebogamma/Flebogamma Dif), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1575Injection, immune globulin/hyaluronidase, (hyqvia), 100 mg immuneglobulin
J1599Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500 mg

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