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Immune Globulin Intravenous (IVIG), Subcutaneous (SCIG)
08.00.13ah

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

INDEX OF MEDICALLY NECESSARY INDICATIONS   
This policy addresses numerous medically necessary indications for the use of Immune Globulin Intravenous (IVIG) and Subcutaneous (SCIG)​​ (listed in order of appearance within the Policy section). Please see below for the specific medical necessity criteria. (NOTE: Other sections such as Experimental/Investigational below must also be reviewed).​

SUBCUTANEOUS IMMUNE GLOBULIN (SCIG)
Immunodeficiency Syndromes
  • Hyperimmunoglobulinemia E syndrome (HIES) (Hyper-IgE syndromes, Job’s syndrome) 
  • Primary immunodeficiency disorders (PIDD)

​Neurological and Musculoskeletal Disorders

  • Chronic inflammatory demyelinating polyneuropathies (CIDP)
​INTRAVENOUS IMMUNE GLOBULIN (IVIG)
Dermatologic
  • Autoimmune mucocutaneous blistering disease for the following biopsy-proven conditions: pemphigus vulgaris, pemphigus foliaceous, bullous pemphigoid, mucous membrane pemphigoid (cicatricial pemphigoid), epidermolysis bullosa acquisita
  • Stevens-Johnson syndrome and toxic epidermal necrolysis
  • Scleromyxedema
Hematologic
  • Acute idiopathic thrombocytopenic purpura (ITP) 
  • Anemia, autoimmune hemolytic (AIHA)
  • Anemia due to parvovirus B19 infection:
  • Chronic refractory idiopathic thrombocytopenic purpura (ITP) 
  • Idiopathic thrombocytopenic purpura (ITP) during pregnancy
  • Fetal/neonatal alloimmune thrombocytopenia
  • Rh and ABO incompatibility (moderate to severe) as treatment in addition to phototherapy to prevent or delay exchange transfusion in neonates
  • Systemic Capillary Leak Syndrome (SCLS) or Clarkson's Disease when associated with monoclonal gammopathy
Immunodeficiency Syndromes, Primary and Secondary
  • Acquired (secondary) hypogammaglobulinemia in oncologic conditions:
    • Chimeric antigen receptor (CAR) T cell ​(anti-CD19) therapy ​
    • Chronic lymphocytic leukemia with associated hypogammaglobulinemia
    • Multiple myeloma with associated hypogammaglobulinemia in an individual who has a high risk of recurrent infections despite prophylactic antibiotic therapy
    • Other malignant diseases with associated hypogammaglobulinemia in an individual who has a high risk of serious, recurrent bacterial infections
  • Acquired von Willebrand disease associated with IgG-MGUS (monoclonal gammopathy of undetermined significance of the IgG Class) or antibody-mediated acquired von Willebrand disease
  • Antineutrophil cytoplasmic antibodies (ANCA)--associated vasculitides (Wegener's Granulomatosis, Microscopic Polyangiitis [MPA], Churg-Strauss syndrome):
  • Autoimmune neutropenia
  • Bone marrow transplantation 
  • Catastrophic antiphospholipid syndrome (CAPS)
  • Coagulopathy due to acquired inhibitor of clotting factor VIII
  • Hematopoietic stem cell transplant (HSCT) for an adult, adolescent, or pediatric allogeneic stem cell transplant recipient who experiences severe hypogammaglobulinemia (IgG less than or equal to 400 mg/dL)
  • Hyperimmunoglobulinemia E syndrome (HIES) (Hyper-IgE syndromes, Job’s syndrome)
  • Human immunodeficiency virus (HIV)--infected individuals to reduce significant bacterial infection 
  • Immune checkpoint inhibitor-related toxicities, management ​
  • Kawasaki disease (mucocutaneous lymph node syndrome)
  • Neonatal hemochromatosis (neonatal alloimmune hepatitis)
  • Primary immunodeficiency disorders (PIDD)
  • Preterm and/or low-birth-weight neonates as prevention for serious infections (including sepsis, urinary tract infection, soft-tissue infections or cellulitis) when severe hypogammaglobulinemia (IgG less than or equal to 400 mg/dL) is present
  • Solid organ transplant amongst sensitized transplant candidates, and antibody-mediated rejection (AMR) 
Infectious Disease
  • Toxic shock syndrome​
Neurological and Musculoskeletal Disorders
  • Acute disseminated encephalomyelitis (ADEM)​
  • Chronic inflammatory demyelinating polyneuropathies (CIDP)
  • Dermatomyositis and polymyositis (PM) 
  • Guillain-Barre syndrome
  • Intractable seizures and epilepsies in infants and children
  • Lambert-Eaton myasthenic syndrome
  • Multifocal motor neuropathy (MMN)
  • Myasthenia gravis syndrome 
  • Myasthenic crisis (i.e., an acute episode of respiratory muscle weakness) 
  • Neuromyelitis Optica (NMO) (Devic’s Syndrome)
  • Rasmussen’s encephalitis
  • Relapsing-remitting multiple sclerosis (MS)
  • Stiff-person syndrome
  • Systemic lupus erythematosus (SLE) ​
MEDICALLY NECESSARY

SUBCUTANEOUS IMMUNE GLOBULIN (SCIG)

 Company-Designated Preferred Products For Primary Immunodeficiency Disorders (PIDD)

Cutaquig, Cuvitru, Hizentra, HyQvia, and Xembify are brand names of subcutaneous immune globulin (SCIG) products that are currently on the market. There are also certain intravenous immune globulin (IVIG) products (e.g., Gammagard Liquid, Gammaked, Gamunex-C) that can be administered intravenously or subcutaneously for primary immunodeficiency disorders (PIDD). Although there are several brands of IVIG and SCIG on the market approved for the treatment of PIDD, there is no reliable evidence of the superiority of any one brand compared to others. The Company has designated Gammagard Liquid, Gammaked, and Gamunex-C as its preferred subcutaneous products. These products are less costly and at least as likely to produce equivalent therapeutic results as the non-preferred products, which include, but are not limited to: Cutaquig, Cuvitru, Hizentra, HyQvia, and Xembify.

Subcutaneous immune globulin (SCIG) (e.g., Cutaquig, Cuvitru, Hizentra, HyQvia, and Xembify) products are considered medically necessary and, therefore, covered for the following indications when the dosing and frequency requirements listed in Attachment A and the following criterion is met:
  • The individual has had a documented failure, contraindication* or intolerance to the subcutaneous administration of The Company's preferred subcutaneous products (i.e., Gammagard Liquid, Gammaked, or Gamunex-C)​
* Contraindications to IG products may include factors such as, but not limited to: volume load, sugar content, sodium content, osmolality, IgA content, or pH.

Immunodeficiency Syndromes
  • Hyperimmunoglobulinemia E syndrome (HIES) (Hyper-IgE syndromes, Job’s syndrome) when all of the following signs and symptoms are present:
    • Individual has eosinophilia (500 or more eosinophils/microL)
    • Individual has elevated serum IgE (>2000 IU/ml), with normal IgG, IgA, and IgM levels
    • Individual has eczema, recurrent staphylococcal lung infections, and/or skin abscesses documented in office or hospital charts
    • Individual has had a documented failure, contraindication* or intolerance to the subcutaneous administration of the Company's preferred subcutaneous products (i.e., Gammagard Liquid, Gammaked, or Gamunex-C) (See "Company-Designated Preferred Products For Primary Immunodeficiency Disorders (PIDD)" section above and "NOT MEDICALLY NECESSARY USES FOR SCIG" section below).
  • Primary immunodeficiency disorders (PIDD)† when the individual has a confirmed genetic diagnosis or laboratory evidence of PIDD or the individual meets both of the following criteria:
    • Individual has a personal history of recurrent, antibiotic-refractory, bacterial infections of the ear (e.g., otitis media) or sinopulmonary infections (e.g., sinusitis, bronchitis/bronchiectasis, pneumonia), which are documented in office or hospital charts
    • Individual has a deficiency of antibody response to at least one of the following antigens (e.g., proteins, polysaccharides, or viral antigens)
      • Polyvalent pneumococcal polysaccharide vaccine (e.g., Pneumovax 23), measured at the time of immunization and 4-8 weeks after vaccination
        • A protective (normal) response to each pneumococcal serotype is defined as a titer equal to or greater than 1.3 mcg/mL antibody.
            1. For individuals ages 6 to 65 years, a normal response is defined as conversion of 70% of the serotypes tested with at least a 2-fold increase in the titers.
            2. For children 24 months through 5 years of age, a normal response is defined as the conversion of 50% or more of the serotypes tested with at least a 2-fold increase in the titers.
            3. (Note: When reported, the conversion factor for nanograms of antibody nitrogen per milliliter (ng N/mL) to antibody micrograms per milliliter is as follows: 160ng N/mL = 1 mcg/mL)
      • Protein antigens, tetanus/diphtheria vaccine measured at the time of immunization and 3 to 4 weeks after vaccination:
        • A protective (normal) response is defined as any of the following:
            1. At least a 4-fold increase for protein antigens
            2. A serum diphtheria antitoxin level of 0.01 International Units (IU)/mL is the lowest level giving some degree of protection, and levels of at least 0.1 IU/mL are generally regarded as protective
            3. A protective level for Tetanus is 0.15 IU/mL
    • Individual has had a documented failure, contraindication* or intolerance to the subcutaneous administration of The Company's preferred subcutaneous products (i.e., Gammagard Liquid, Gammaked, or Gamunex-C) (See "Company-Designated Preferred Products For Primary Immunodeficiency Disorders (PIDD)" section above and "NOT MEDICALLY NECESSARY USES FOR SCIG" section below).
    †The list of PIDDs includes, but is not limited to:
      1. Ataxia-telangectasia
      2. Autosomal recessive agammaglobulinemia
      3. Caspase 8 deficiency
      4. Common variable immunodeficiency (including TACI and ICOS mutation)
      5. DiGeorge syndrome
      6. DOCK (dedicator of cytokinesis 8) deficiency
      7. Griscelli syndrome
      8. Hypogammaglobulinemia, persistent (IgG less than or equal to 400 mg/dL or less than two standard deviations from normal)
      9. IgG-subclass deficiency (deficiency of one or more IgG subclasses to levels less than 2 standard deviations below the age-specific mean, in the presence of normal or near-normal total IgG levels). (These levels must be assessed on at least two occasions while the individual is free of acute infections.)
      10. NEMO (mutations in IKK-gamma) deficiency
      11. Nijmegen breakage syndrome
      12. Purine nucleoside phosphorylase [PNP] deficiency
      13. Selective IgA deficiency with IgG subclass deficiency (reduced serum IgA levels [less than 7mg/dL] and normal IgG and IgM levels)
      14. Severe combined immunodeficiency (SCID)
      15. Specific antibody deficiency (Selective antibody deficiency) with normal immunoglobulins
        1. Individual has impaired production of specific antibodies to polysaccharide antigens after vaccination and normal responses to protein antigens
      16. Transient hypogammaglobulinemia of infancy
      17. WHIM (warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis) syndrome
      18. Wiskott-Aldrich syndrome
      19. X-linked agammaglobulinemia (aka, Bruton's agammaglobulinemia, congenital agammaglobulinemia)
      20. X-linked and autosomal recessive hyper IgM syndromes
      21. X-linked immunodeficiency
      22. X-linked lymphoproliferative disease
Neurological and Musculoskeletal Disorders
  • Chronic inflammatory demyelinating polyneuropathies (CIDP)
    • Individual will begin treatment with SCIG after transitioning from IVIG.
    • There must be objective clinical evidence to support the diagnosis of CIDP (such as impaired function measured by a standard clinical scale at the time of initial therapy [e.g., slowing of nerve conduction velocity on electromyography, nerve conduction studies]).
    • Individual has had a documented failure, contraindication* or intolerance to the subcutaneous administration of The Company's preferred subcutaneous products (i.e., Gammagard Liquid, Gammaked, or Gamunex-C) (See "Company-Designated Preferred Products For Primary Immunodeficiency Disorders (PIDD)" section above and "NOT MEDICALLY NECESSARY USES FOR SCIG" section below).
INTRAVENOUS IMMUNE GLOBULIN (IVIG)
Use of intravenous immune globulin (IVIG) therapy (e.g., Asceniv, Bivigam, Flebogamma, Gammagard Liquid, Gammagard S/D, Gammaked, Gammaplex, Gamunex-C, Octagam, Panzyga, Privigen) is considered medically necessary and, therefore, covered for the following indications when the dosing and frequency requirements listed in Attachment A and the following criteria are met:

Dermatologic
  • Autoimmune mucocutaneous blistering disease for the following biopsy-proven conditions: pemphigus vulgaris, pemphigus foliaceous, bullous pemphigoid, mucous membrane pemphigoid (cicatricial pemphigoid), epidermolysis bullosa acquisita when one of the following criteria is met:
    • The individual failed conventional therapy (e.g., steroids, methotrexate, immunosuppressive therapy) or conventional therapy is contraindicated.
    • The individual has a rapidly progressive disease in which a clinical response could not be effected quickly enough using conventional agents. In this case, IVIG is given along with conventional treatments, and IVIG would be used only until conventional therapy could take effect.
    IVIG for the treatment of autoimmune mucocutaneous blistering disease must be used for short-term therapy, not maintenance therapy.
  • Stevens-Johnson syndrome and toxic epidermal necrolysis
  • Scleromyxedema
Hematologic
  • Acute idiopathic thrombocytopenic purpura (ITP) when one of the following criteria is met:
    • The individual requires a rapid platelet count increase (e.g., prior to surgical procedures, to control excessive bleeding, to defer or avoid a splenectomy).
    • The individual has acute bleeding due to severe thrombocytopenia (platelet counts usually less than 30,000/mm3).
    • The individual has severe thrombocytopenia (platelet counts less than 20,000/mm3) and is considered at risk for intracerebral hemorrhage.
  • Anemia, autoimmune hemolytic (AIHA) when the following criterion is met:
    • The individual has had prior treatment with corticosteroids and/or splenectomy, unless contraindicated.
  • Anemia due to parvovirus B19 infection:
    • In individuals with chronic parvovirus B19 infection and severe anemia associated with bone marrow suppression
  • Chronic refractory idiopathic thrombocytopenic purpura (ITP) when all of the following criteria are met:
    • The individual has a disease duration of greater than six (6) months.
    • The individual has no concurrent illness or disease to explain the thrombocytopenia.
    • The individual has platelet counts that remain persistently at or below 20,000/mm3.
    • The individual has had splenectomy and/or prior treatment with corticosteroids, unless documented failure, contraindication, or intolerance to corticosteroids exists.
  • Idiopathic thrombocytopenic purpura (ITP) during pregnancy when one of the following criteria is met:
    • The individual has previously delivered infants with autoimmune thrombocytopenia.
    • The individual's platelet counts are less than 50,000/mm3 during the current pregnancy.
    • The individual has a history of splenectomy.​
  • Fetal/neonatal alloimmune thrombocytopenia
  • Rh and ABO incompatibility (moderate to severe) as treatment in addition to phototherapy to prevent or delay exchange transfusion in neonates
  • Systemic Capillary Leak Syndrome (SCLS) or Clarkson's Disease when associated with monoclonal gammopathy
Immunodeficiency Syndromes, Primary and Secondary
  • Acquired (secondary) hypogammaglobulinemia in oncologic conditions:
    • Chimeric antigen receptor (CAR) T cell ​(anti-CD19) therapy (e.g., axicabtagene ciloleucel [Yescarta], brexucabtagene autoleucel [Tecartus], lisocabtagene maraleucel [Breyanzi], tisagenlecleucel [Kymriah®]) acquired hypogammaglobulinemia when the individual has an IgG level of less than 400-600 mg/dL and serious or recurrent infections (particularly bacterial)​
    • Chronic lymphocytic leukemia with associated hypogammaglobulinemia when one of the following criteria is met:
      • The individual has an IgG level of less than 600 mg/dL.
      • The individual presents evidence of a specific antibody deficiency.
      • The individual presents with serious, recurrent bacterial infections.
    • Multiple myeloma with associated hypogammaglobulinemia in an individual who has a high risk of recurrent infections despite prophylactic antibiotic therapy
    • Other malignant diseases with associated hypogammaglobulinemia in an individual who has a high risk of serious, recurrent bacterial infections
  • Acquired von Willebrand disease associated with IgG-MGUS (monoclonal gammopathy of undetermined significance of the IgG Class) or antibody-mediated acquired von Willebrand disease in individuals in life-threatening situations or prior to surgery when treatment of the underlying condition is not possible.
    • Documented failure, contraindication, or intolerance to standard treatment (e.g., desmopressin and von Willebrand factor replacement)
  • Antineutrophil cytoplasmic antibodies (ANCA)--associated vasculitides (Wegener's Granulomatosis, Microscopic Polyangiitis [MPA], Churg-Strauss syndrome):
    • The individual is unresponsive/refractory to, intolerant of, or has a contraindication to other standard therapies (e.g., corticosteroids, immunosuppressants).
  • Autoimmune neutropenia
  • Bone marrow transplantation when both of the following criteria are met:
    • The individual is 20 years of age or older and has had a transplant for a covered indication.
    • The individual received the transplant within the past 90 days.
  • Catastrophic antiphospholipid syndrome (CAPS) when all of the following criteria are met:
    • The condition is life-threatening.
    • The individual has severe thrombocytopenia and features of microangiopathy (e.g., thrombocytopenia, microangiopathic hemolytic anemia).
    • The individual is unresponsive/refractory to, intolerant of, or has a contraindication to other standard therapies (i.e., corticosteroids and anticoagulants).
    • IVIG must be used in combination with plasma exchange.
  • Coagulopathy due to acquired inhibitor of clotting factor VIII
  • Hematopoietic stem cell transplant (HSCT) for an adult, adolescent, or pediatric allogeneic stem cell transplant recipient who experiences severe hypogammaglobulinemia (IgG less than or equal to 400 mg/dL)
  • Hyperimmunoglobulinemia E syndrome (HIES) (Hyper-IgE syndromes, Job’s syndrome) when all of the following signs and symptoms are present:
    • Individual has eosinophilia (500 or more eosinophils/microL).
    • Individual has elevated serum IgE (>2000 IU/ml), with normal IgG, IgA, and IgM levels.
    • Individual has eczema, recurrent staphylococcal lung infections, and/or skin abscesses documented in office or hospital charts.
  • Human immunodeficiency virus (HIV)--infected individuals to reduce significant bacterial infection when all of the following criteria are met:
    • The individual is younger than 14 years of age.
    • The individual has entry CD4 lymphocyte counts greater than or equal to 200/mm³.
    • The individual is clinically symptomatic or asymptomatic, but is immunologically abnormal.
    • The individual has severe hypogammaglobulinema (serum IgG level less than 400 mg/dL) and/or functional antibody deficiency demonstrated by either poor specific antibody titers or recurrent bacterial infections.
    • The individual has recurrent serious bacterial infections, (i.e., two or more infections such as bacteremia, meningitis, or pneumonia in a one year period).
  • Immune checkpoint inhibitor-related toxicities, management ​(Note: examples of immune checkpoint inhibitors include, but are not limited to: ipilimumab [Yervoy], PD-1/PD-L1 inhibitors [e.g., atezolizumab [Tecentriq], nivolumab [Opdivo], pembrolizumab [Keytruda]) 
    • Suspected myocarditis​, as additional therapy if no improvement within 24 hours of starting pulse-dose methylprednisolone  
    • Severe (Grade 3) or life-threatening (Grade 4) bullous dermatitis
    • Stevens-Johnson syndrome, or toxic epidermal necrolysis
    • ​Severe (Grade 3-4) myasthenia gravis
    • Severe (Grade 3-4) pneumonitis if no improvement after 48 hours of methylprednisolone 
    • Moderate (Grade 2) or severe (Grade 3-4) Guillain-Barré Syndrome or severe (Grade 3-4) peripheral neuropathy in combination with pulse-dose methylprednisolone
    • Encephalitis in combination with pulse-dose methylprednisolone if severe or progressing symptoms, or if oligoclonal bands present
    • Transverse myelitis
    • Moderate, severe, or life-threatening steroid-refractory myalgias or myositis
  • Kawasaki disease (mucocutaneous lymph node syndrome)
  • Neonatal hemochromatosis (neonatal alloimmune hepatitis):
    • Administration to pregnant women with history of pregnancy ending in documented neonatal hemochromatosis who are at risk for subsequent pregnancies ending in documented neonatal hemochromatosis
    • Administration to the neonate with documented neonatal hemochromatosis, combined with exchange transfusion
  • Primary immunodeficiency disorders (PIDD)† when the individual has a confirmed genetic diagnosis or laboratory evidence of PIDD or the individual meets both of the following criteria:
    • Individual has a personal history of recurrent, antibiotic-refractory, bacterial infections of the ear (e.g., otitis media) or sinopulmonary infections (e.g., sinusitis, bronchitis/bronchiectasis, pneumonia), which are documented in office or hospital charts.
    • Individual has a deficiency of antibody response to at least one of the following antigens (e.g., proteins, polysaccharides, or viral antigens):
      • Polyvalent pneumococcal polysaccharide vaccine (e.g., Pneumovax 23), measured at the time of immunization and four to eight (4-8) weeks after vaccination.
        • A protective (normal) response to each pneumococcal serotype is defined as a titer equal to or greater than 1.3 mcg/mL antibody.
            1. For individuals ages six to 65 years, a normal response is defined as conversion of 70% of the serotypes tested with at least a two-fold increase in the titers.
            2. For children 24 months through 5 years of age, a normal response is defined as the conversion of 50% or more of the serotypes tested with at least a two-fold increase in the titers.
            3. (Note: When reported, the conversion factor for nanograms of antibody nitrogen per milliliter (ng N/mL) to antibody micrograms per milliliter is as follows: 160ng N/mL = 1 mcg/mL)
      • Protein antigens, tetanus/diphtheria vaccine measured at the time of immunization and 3 to 4 weeks after vaccination
        • A protective (normal) response is defined as any of the following:
            1. At least a four-fold increase for protein antigens
            2. A serum diphtheria antitoxin level of 0.01 International Units (IU)/mL is the lowest level giving some degree of protection, and levels of at least 0.1 IU/mL are generally regarded as protective
            3. A protective level for Tetanus is 0.15 IU/mL
      †The list of PIDDs includes, but is not limited to:
        1. Ataxia-telangectasia
        2. Autosomal recessive agammaglobulinemia
        3. Caspase 8 deficiency
        4. Common variable immunodeficiency (including TACI and ICOS mutation)
        5. DiGeorge syndrome
        6. DOCK (dedicator of cytokinesis 8) deficiency
        7. Griscelli syndrome
        8. Hypogammaglobulinemia, persistent (IgG less than or equal to 400 mg/dL or less than two standard deviations from normal)
        9. IgG-subclass deficiency (deficiency of one or more IgG subclasses to levels less than 2 standard deviations below the age-specific mean, in the presence of normal or near-normal total IgG levels). (These levels must be assessed on at least two occasions while the individual is free of acute infections.)
        10. NEMO (mutations in IKK-gamma) deficiency
        11. Nijmegen breakage syndrome
        12. Purine nucleoside phosphorylase [PNP] deficiency
        13. Selective IgA deficiency with IgG subclass deficiency (reduced serum IgA levels [less than 7mg/dL] and normal IgG and IgM levels)
        14. Severe combined immunodeficiency (SCID)
        15. Specific antibody deficiency (Selective antibody deficiency) with normal immunoglobulins
          1. Individual has impaired production of specific antibodies to polysaccharide antigens after vaccination and normal responses to protein antigens
        16. Transient hypogammaglobulinemia of infancy
        17. WHIM (warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis) syndrome
        18. Wiskott-Aldrich syndrome
        19. X-linked agammaglobulinemia (aka, Bruton's agammaglobulinemia, congenital agammaglobulinemia)
        20. X-linked and autosomal recessive hyper IgM syndromes
        21. X-linked immunodeficiency
        22. X-linked lymphoproliferative disease
  • Preterm and/or low-birth-weight neonates as prevention for serious infections (including sepsis, urinary tract infection, soft-tissue infections or cellulitis) when severe hypogammaglobulinemia (IgG less than or equal to 400 mg/dL) is present
  • Solid organ transplant amongst sensitized transplant candidates, ​and antibody-mediated rejection (AMR) when the individual has had a transplant
Infectious Disease
  • Toxic shock syndrome
    • IVIG may be considered an adjunct in the treatment of staphylococcal or streptococcal toxic shock syndrome.
Neurological and Musculoskeletal Disorders
  • Acute disseminated encephalomyelitis (ADEM)
    • Rescue therapy for individuals unresponsive/refractory to, intolerant of, or who have a contraindication to, corticosteroids.
  • Chronic inflammatory demyelinating polyneuropathies (CIDP)
    • There must be objective clinical evidence to support the diagnosis of CIDP (such as impaired function measured by a standard clinical scale at the time of initial therapy [e.g., slowing of nerve conduction velocity on electromyography, nerve conduction studies]).
  • Dermatomyositis and polymyositis (PM) when all of the following criteria are met:
    • There must be clinical evidence to support the diagnosis, as well as a biopsy (or unequivocal diagnostic features through history, exam, and EMG/NCS studies) performed to verify the diagnosis of dermatomyositis or polymyositis.
    • The individual has impaired function (such as a decrease in muscle strength and/or electromyography abnormalities measured by a standard clinical scale at the time of initial therapy) and/or elevated serum Creatine Kinase (CK) levels.
    • The individual is unresponsive/refractory to, intolerant of, or has a contraindication to, a four month trial of steroids and/or immunosuppressants.
  • Guillain-Barre syndrome
    • The individual's function is impaired (e.g., unable to stand or walk without aid), measured by a standard clinical scale and/or objective findings on a physical exam at the time of initial therapy.
  • Intractable seizures and epilepsies in infants and children
    • The individual is unresponsive/refractory to, intolerant of, or has a contraindication to, all standard therapies (e.g., antiepileptic drugs and corticosteroids).
  • Lambert-Eaton myasthenic syndrome
    • The individual is unresponsive/refractory to, intolerant of, or has a contraindication to, other standard therapies (e.g., plasma exchange, corticosteroids or other immunosuppressants, cholinesterase inhibitors, or 3,4-diaminopyridine [DAP]).
  • Multifocal motor neuropathy (MMN)
    • The individual has progressive, symptomatic MMN that has been diagnosed on the basis of electrophysiologic findings that rule out other possible conditions that may not respond to IVIG.
  • Myasthenia gravis syndrome when all of the following criteria are met:
    • The individual has severely impaired function (such as a risk of respiratory failure) measured by a standard clinical scale and/or objective findings on a physical exam at the time of initial therapy.
    • The individual is refractory to other standard therapies (e.g., plasmapheresis) or to standard pharmacological therapies (e.g., corticosteroids, azathioprine, cyclosporine, cyclophosphamide, cholinesterase inhibitors) given in therapeutic doses over at least 8 weeks or is intolerant of, or has a contraindication to, standard therapies.
  • Myasthenic crisis (i.e., an acute episode of respiratory muscle weakness) in individuals with contraindication to plasma exchange
  • Neuromyelitis Optica (NMO) (Devic’s Syndrome)
    • The individual is unresponsive/refractory to, intolerant of, or has a contraindication to ​other standard therapies (e.g., corticosteroids and azathioprine).
  • Rasmussen’s encephalitis
    • In patients with intractable focal motor seizures and progressive neurologic deterioration (dementia, hemiparesis)
  • Relapsing-remitting multiple sclerosis (MS) when all of the following criteria are met:
    • The individual has impaired function measured by a standard clinical scale and/or objective findings on a physical exam at the time of initial therapy.
    • The individual is refractory to other standard therapies (e.g., interferons) given in therapeutic doses over at least three (3) months, or is intolerant of, or has a contraindication to, standard therapies.
    • The individual has an acute relapse of the disease.
  • Stiff-person syndrome
    • The individual is refractory to other standard therapies (e.g., muscle relaxants, benzodiazepines, and gabapentin-related medications)
  • Systemic lupus erythematosus (SLE) in an individual who failed previous treatment such as corticosteroids and immunosuppressive agents, or treatment was ineffective or contraindicated
CONTINUATION OF THERAPY FOR IVIG, SCIG

Once treatment with immune globulin (IVIG, SCIG) is initiated, documentation of the individual's progress is required. If there is initial improvement and continued treatment is necessary, then objective clinical assessment to monitor the progress is required. Objective monitoring may be done with any accepted clinical method such as the Medical Research Council (MRC) scale, Rankin score, Activities of Daily Living (ADL) scores, and/or objective findings on physical exam. Changes in these measures and the relationship of the change to immune globulin use are expected to be documented clearly. Subjective improvement is insufficient to continue immune globulin treatment. Clinical monitoring takes clear precedence over laboratory monitoring. If clinical improvement is evident, then laboratory monitoring solely to guide immune globulin therapy is not necessary.

MANDATES 
 
PENNSYLVANIA MEMBERS
In accordance with the Commonwealth of Pennsylvania's >Act 6 of 2020< or >Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive agents (08.01.08) for additional information regarding the applicable coverage of drugs and biologics.

NOT MEDICALLY NECESSARY USES FOR SCIG

Coverage of non-preferred products (e.g., Cutaquig, Cuvitru, Hizentra, HyQvia, and Xembify) are considered not medically necessary and, therefore, not covered for the treatment of PIDD because there is no reliable evidence of the superiority of any one brand compared to others and more cost-effective alternatives are available. An exception would be considered if the individual has had a documented failure, contraindication*, or intolerance to the subcutaneous administration of the Company's preferred subcutaneous products (i.e., Gammagard Liquid, Gammaked, or Gamunex-C).

EXPERIMENTAL/INVESTIGATIONAL USES FOR IVIG, SCIG

All other uses of immune globulin (IVIG, SCIG), including the list below, are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the policy on off-label coverage for prescription drugs and biologics.
  • Alzheimer's disease
  • Autism
  • Autoimmune encephalopathy
  • Hemolytic uremic syndrome
  • Multiple sclerosis: Primary Progressive or Secondary Progressive
  • Myocarditis (Acute)
  • Neonatal sepsis treatment
  • Paraneoplastic limbic encephalitis
  • Pediatric Acute-onset Neuropsychiatric Syndrome (PANS)
  • Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)
  • Pericarditis refractory, recurrent
  • Peripheral neuropathy of unknown etiology with peroneal muscle atrophy
  • Postural tachycardia syndrome (POTS)
  • Yellow nail syndrome
NOT ELIGIBLE FOR REIMBURSEMENT

Carimune NF and Vivaglobin are ​no longer manufactured and have been withdrawn from the market; therefore, they are not eligible for reimbursement.​

DOSING AND FREQUENCY REQUIREMENTS

The Company reserves the right to modify the Dosing and Frequency Requirements listed in this Policy to ensure consistency with the most recently published recommendations for the use of IVIG and SCIG. Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to the US Food and Drug Administration (FDA), drug manufacturer’s guidelines, Company- recognized authoritative pharmacology compendia, or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of IVIG and SCIG outside of the Dosing and Frequency Requirements listed in this policy. For a list of Company-recognized pharmacology compendia and criteria for peer-reviewed clinical research, view our policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of these drugs. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the precertification process. The Company reserves the right to conduct post-payment review and audit procedures for any claims submitted for IVIG and SCIG.

Refer to Attachment A for dosing and frequency requirements for IVIG and SCIG.

REQUIRED DOCUMENTATION

When coverage of IVIG and SCIG is requested outside of the Dosing and Frequency Guidelines listed in this policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.

The Company may conduct reviews and audits of services to our members regardless of the participation status of the provider. Medical record documentation must be maintained on file to reflect the medical necessity of the care and services provided. These medical records may include but are not limited to: records from the professional provider’s office, hospital, nursing home, home health agencies, therapies, and test reports.

PRESCRIPTION (ORDER) REQUIREMENTS
Before submitting a claim to the Company, the supplier must have on file a timely, appropriate, and complete order for each item billed that is signed and dated by the professional provider who is treating the member. Requesting a provider to sign a retrospective order at the time of an audit or after an audit for submission as an original order, reorder, or updated order will not satisfy the requirement to maintain a timely professional provider order on file.

PROOF OF DELIVERY
Medical record documentation must include a contemporaneously prepared delivery confirmation or member’s receipt of supplies and equipment. The medical record documentation must include a copy of delivery confirmation if delivered by a commercial carrier and a signed copy of delivery confirmation by member/caregiver if delivered by the durable medical equipment (DME) supplier/provider. All documentation is to be prepared contemporaneous with delivery and be available to the Company upon request.

CONSUMABLE SUPPLIES
The DME supplier must monitor the quantity of accessories and supplies an individual is actually using. Contacting the individual regarding replenishment of supplies should not be done earlier than approximately seven days prior to the delivery/shipping date. Dated documentation of this contact with the individual is required in the individual’s medical record. Delivery of the supplies should not be done earlier than approximately five days before the individual would exhaust their on-hand supply.

If required documentation is not available on file to support a claim at the time of an audit or record request, the DME supplier may be required to reimburse the Company for overpayments.

Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, intravenous immune globulin (IVIG) and subcutaneous immune globulin (SCIG) are covered under the medical benefits of the Company’s products when the medical necessity criteria, dosing and frequency requirements, and precertification/preapproval requirements listed in this medical policy are met.

However, indications that are identified in this policy as experimental/investigational are not eligible for coverage or reimbursement by the Company.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

The FDA has approved numerous formulations of IVIG and SCIG.

In 1994, the FDA approved Gammagard S/D for the treatment of PIDD. Supplemental approvals for Gammagard S/D® have since been issued by the FDA.

In 2003, the FDA approved both Gamunex-C and Gammaked immune globulin intravenous (IVIG) (human) 10 percent liquid products for the treatment of PIDD via intravenous or subcutaneous administration. Supplemental approvals for both products have since been issued by the FDA.

On December 15, 2003, the FDA approved Flebogamma IVIG (human) for the treatment of PIDD. Supplemental approvals for Flebogamma® have since been issued by the FDA.

On May 21, 2004, the FDA approved Octagam IVIG (human) 5 percent liquid product for the treatment of PIDD. Supplemental approvals for Octagam® have since been issued by the FDA.

In 2005, the FDA approved Gammagard Liquid IVIG (human) 10 percent liquid product for the treatment of PIDD via intravenous or subcutaneous administration. Supplemental approvals for Gammagard Liquid® have since been issued by the FDA.

On July 26, 2007, the FDA approved Privigen, IVIG (human) 10 percent liquid product for the treatment of PIDD and chronic ITP.

On September 17, 2009 the FDA approved Gammaplex IVIG (human) 5 percent liquid product for the treatment of PIDD. A subsequent approval for the treatment of chronic ITP was granted on March 8, 2013.

On March 4, 2010, the FDA approved Hizentra SCIG (human) 20 percent liquid product for the treatment of PIDD. Supplemental approvals for Hizentra® have since been issued by the FDA.

On December 19, 2012, the FDA approved Bivigam IVIG (human) 10 percent liquid product for the treatment of PIDD.

On September 12, 2014, the FDA approved HyQvia SCIG (human) with Recombinant Human Hyaluronidase) 10 percent liquid product for the treatment of PIDD.

On September 13, 2016, the FDA approved Cuvitru SCIG (human) 20 percent solution for the treatment of PIDD.

On August 2, 2018, the FDA approved Panzyga, Immune Globulin Intravenous, human-ifas, 10% Solution for the treatment of PIDD and chronic ITP.

On December 12, 2018, the FDA approved Cutaquig, Immune Globulin Subcutaneous (Human), 16.5% Solution for the treatment of PIDD.

On April 1, 2019, the FDA approved Asceniv, Immune Globulin Intravenous, human-slra, 10% Solution for the treatment of PIDD.

On July 3, 2019, the FDA approved Xembify, Immune Globulin Subcutaneous, human-klhw, 20% Solution for the treatment of PIDD.

Description

Intravenous immune globulin (IVIG) is a sterile solution of plasma proteins containing immune globulin G (IgG) antibodies from pooled human plasma. The preparation contains no less than 90 percent of immune globulin consisting of all IgG substances and trace amounts of immune globulin A (IgA) and immune globulin M (IgM). IVIG supplies a broad spectrum of IgG antibodies against a wide variety of bacterial and viral agents. IVIG has been used to correct immune deficiencies and to increase immunity in diseases considered to have an autoimmune basis. IVIG is administered in this form and with this route of administration when immediate increase or higher levels of circulating immune globulin are required and cannot be attained from intramuscular administration, or when the latter is contraindicated.

The US Food and Drug Administration (FDA) has approved the subcutaneous infusion preparation of an immune globulin product (SCIG) for the prevention of serious infections in those with primary immunodeficiency disease (PIDD). SCIG is administered subcutaneously using an infusion pump, usually on a weekly basis, in CIDP and PIDD. SCIG may be an option for individuals who have received IVIG and wish to transition to the subcutaneous infusion route. When transitioning from IVIG to a SCIG formulation, the weekly dose of Ig must be increased for some of the SCIG formulations; hence, SCIG formulations utilize more grams of Ig compared to IVIG formulations.

Note: There are a few formulations of IVIG that may be administered via subcutaneous infusion for the indication of PIDD (e.g., Gammagard Liquid®, Gamunex-C®, Gammaked®).

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

REFERENCES FOR MEDICALLY NECESSARY INDICATIONS

Absoud M, Brex P, Ciccarelli O,et al. A multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin compared with standard therapy for the treatment of transverse myelitis in adults and children (STRIVE). Health Technol Assess. 2017 May;21(31):1-50.

Ahmed AR, Nguyen T, Kaveri S, et al. First line treatment of pemphigus vulgaris with a novel protocol in patients with contraindications to systemic corticosteroids and immunosuppressive agents: Preliminary retrospective study with a seven year follow-up. Int Immunophjarmacol. 2016;34:25-31.

Allenspach E, Rawlings DJ, Scharenberg AM. X-linked severe combined immunodeficiency. 2003 [Updated 2016]. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReview.

Alhamad T, Kukla A, Stratta RJ. Pancreas-kidney transplantation in diabetes mellitus: pancreas allograft rejection. UpToDate Website. 02/27/2020. Available at: https://www.uptodate.com/contents/pancreas-allograft-rejection?source=search_result&search=antibody mediated rejection&selectedTitle=10~150. Accessed November 4, 2021. 

Alsaleem M. Intravenous Immune Globulin Uses in the Fetus and Neonate: A Review. Antibodies (Basel). 2020 Nov 4;9(4):60. 

Altunrende B, Akdal G, Bajin MS, et al. Intravenous Immunoglobulin Treatment for Recurrent Optic Neuritis. Noro Psikiyatr Ars. 2019 Mar;56(1):3-6. 

 Alzueta, IJ and Matamoros, FN. Common Variable Immunodeficiency. Review. Allergol Immunopathol (Madr). 2001 May-Jun;29(3) 113-8.

Amagai M, Ikeda S, Hashimoto T, et al. A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid. J Dermatol Sci. 2017;85:77-84.

American Academy of Allergy, Asthma & Immunology (AAAAI). Work Group Report on the appropriate use of intravenously administered immunoglobulin (IGIV). August 2005.

American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1) 297-316.

American Hospital Formulary Service (AHFS). Drug Information 2021. Immune Globulin. updated 02/08/2021. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed September 13, 2021. 

Amrouche L, Aubert D, Suberbielle C, et al. Long-term outcomes of kidney transplantation in patients with high levels of preformed DSA: the Necker high-risk transplant program. Transplantation. 2017;Jan 21.

Anh-Tu Hoa S, Hudson M. Critical review of the role of intravenous immunoglobulins in idiopathic inflammatory myopathies. Semin Arthritis Rheum. 2017;46:488-508.

Axicabtagene ciloleucel (Yescarta). Kite Pharma, Inc.: Santa Monica, CA. Prescribing Information. 04/2021. Available at: https://www.yescartahcp.com/large-b-cell-lymphoma . Accessed November 4, 2021. 

Bakker J, Metz L. Devic’s neuromyelitis optica treated with intravenous gamma globulin (IVIG). Can J Neurol Sci. 2004;31 265-267.

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Ballow M, Fleisher TA. Secondary immunodeficiency induced by biologic therapies. UpToDate Website. 04/02/2021. Available at: https://www.uptodate.com/contents/secondary-immunodeficiency-induced-by-biologic-therapies?source=search_result&search=secondary immunodeficiency&selectedTitle=3~74. Accessed November 4, 2021. 

Barcellini W. Immune hemolysis: Diagnosis and treatment recommendations. Semin Hematol. 2015;52:304-312.

Barron SJ, Del Vecchio MT, Aronoff SC. Intravenous immunoglobulin in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: a meta-analysis with meta-regression of observational studies. Int J Dermatol. 2015;54(1):108-15. Review.

Bayry J, Hartung HP, Kaveri SV. FORUM IVIg for relapsing-remitting multiple sclerosis: promises and uncertainties. Trends Pharmacol Sci. 2015;36(7):419-21.

Bello-Espinosa LE, Rajapakse T, Rho JM, et al. Efficacy of intravenous immunoglobulin in a cohort of children with drug-resistant epilepsy. Pediatr Neurol. 2015;52:509-516.

Bennett CM, Neunert C, Grace RF, et al. Predictors of remission in children with newly diagnosed immune thrombocytopenia: Data from the Intercontinental Cooperative ITP Study Group Registry II participants. Pediatr Blood Cancer. 2018 Jan;65(1).

Berger T, Jacobi C, Haas J, et al. Predicting therapeutic efficacy of intravenous immunoglobulin (IVIG) in individual patients with relapsing remitting multiple sclerosis (RRMS) by functional genomics. J Neuroimmunol. 2014;277(1-2):145-52.

Bhat V, Joshi A, Sarode R, et al. Cytomegalovirus in the bone marrow transplant patient. World J Transplant. 2015 Dec 24;5(4):287-91.

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Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Compendium 02/12/13. 

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Brandt-Wouters E, Gerlach OH, Hupperts RM. The effect of postpartum intravenous immunoglobulins on the relapse rate among patients with multiple sclerosis. Int J Gynaecol Obstet. 2016;134:194-196.

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Buckley RH, Orange JS. Primary immunodeficiency disease. In: Adkinson NF, Bochner BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, O'Hehir RE, eds. Middleton's Allergy: Principles and Practice, 8th Edition. Philadelphia, PA: Elsevier Saunders; 2013, Chapter 72.

Burton SA, Amir N, Asbury A, et al. Treatment of antibody-mediated rejection in renal transplant patients: a clinical practice survey. Clin Transplant 2015;29:118-123.

Bussel JB. Immune thrombocytopenia (ITP) in children: Management of chronic disease. UpToDate Website. 06/11/19. Available at: https://www.uptodate.com/contents/immune-thrombocytopenia-itp-in-children-management-of-chronic-disease?source=search_result&search=ITP&selectedTitle=3~150. Accessed November 4, 2021. 

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Carapetis JR, Jacoby P, Carville K, et al. Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group a streptococcal infections. Clin Infect Dis. 2014;59:359-365.

Centers for Medicare and Medicaid Services (CMS). MM11295 – Update to Coverage of Intravenous Immune Globulin for Treatment of Primary Immune Deficiency Diseases in the Home; effective 08/13/2019.

Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of the CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR.2000;49(No. RR-10):1-147.

Centers for Medicare and Medicaid Services (CMS). Medicare Benefit Policy Manual. Chapter 15 – Covered Medical and Other Health Services. 50.6 – Coverage of Intravenous Immune Globulin for Treatment of Primary Immune Deficiency Diseases in the Home. (Rev.:11693, Issued:11-09-22, Effective: 10-01-22, Implementation: 12-12-22). Available at: https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/bp102c15.pdf . Accessed December 15, 2022.

Centers for Medicare and Medicaid Services (CMS). National Coverage Determination (NCD). 250.3 NCD for intravenous immune globulin for the treatment of autoimmune mucocutaneous blistering diseases. [CMS Web Site]. 10/01/02. Available at: http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=158&ncdver=1&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=Pennsylvania&KeyWord=Immune+Globulin&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAAAAAAAA==&.  Accessed September 9, 2021.​​

Cervera R, Rodríguez-Pintó I, Espinosa G. The diagnosis and clinical management of the catastrophic antiphospholipid syndrome: A comprehensive review. J Autoimmun. 2018 Aug;92:1-11. 

Chen KY, Cheung M, Burgner DP, et al. Toxic shock syndrome in Australian children. Arch Dis Child. 2016;101:736-740.

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Coates TD. Immune neutropenia. UpToDate. 04/14/20. Available at: https://www.uptodate.com/contents/immune-neutropenia?source=search_result&search=autoimmune neutropenia&selectedTitle=1~50. Accessed October 12, 2021.

Colvin MM, Cook JL, Chang P, et al. Antibody-mediated rejection in cardiac transplantation: Emerging knowledge in diagnosis and management. A scientific statement from the American Heart Association. Circulation. 2015;131:1608-1639.

Cooper N. State of the art – how I manage immune thrombocytopenia. Br J Haematol. 2017;177:39-54.

Coutre S. Acquired inhibitors of coagulation. 12/04/2020. Available at: https://www.uptodate.com/contents/acquired-inhibitors-of-coagulation?source=search_result&search=coagulopathy+acquired+VIII+clotting+AND+IVIG&selectedTitle=1~150 [via subscription only]. Accessed October 12, 2021.​

Cutaquig. Immune Globulin Subcutaneous (Human), 16.5% Solution. Approval and prescribing information. Octapharma USA INC.:Paramus, NJ. 07/2020. Available at: https://www.cutaquigus.com/ . Accessed September 13, 2021.

Cuvitru, Immune Globulin Subcutaneous (Human), 20% Solution approval and prescribing information. Baxalta US Inc.: Lexington, MA. 03/2021. Available at: https://www.cuvitru.com/ . Accessed September 13, 2021.

Dalakas M. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19) 2367-75.

de Chambrun MP, Gousseff M, Mauhin W, Lega JC, Lambert M, Rivière S, et al. Intravenous immunoglobulins improve survival in monoclonal gammopathy-associated systemic capillary-leak syndrome. Am J Med 2017;130(10):1219.e19-1219.e.27.

De Sousa-Amorim E, Revuelta I, Blasco M, et al. Desensitization before living donor kidney transplantation in highly HLA-sensitized patients: A single center study. Transplant Proc. 2015;47:2332-2335.

Dhawan PS, Goodman BP, Harper CM, et al. IVIG versus PLEX in the treatment of worsening myasthenia gravis: What is the evidence?: A critically appraised topic. Neurologist. 2015;19:145-148.

Doan A, Pulsipher MA. Hypogammaglobulinemia due to CAR T-cell therapy. Pediatr Blood Cancer. 2018 Apr;65(4).

Druey KM, Parikh SM. Idiopathic systemic capillary leak syndrome (Clarkson disease). J Allergy Clin Immunol. 2017 Sep;140(3):663-670.

Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2013 Dec 30;12:CD001797.

Elovaara I, Kuusisto H, Wu X, et al.Intravenous immunoglobulins are a therapeutic option in the treatment of multiple sclerosis relapse. Clin Neuropharmacol. 2011;34(2) 84-9.

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Elsevier’s Clinical Pharmacology Compendium. Immune Globulin SC, SCIG, IGSC. [Clinical Key Web site]. 04/30/2021. Available at: https://www.clinicalkey.com/pharmacology/monograph/3470?sec=monindi#233 [via subscription only]. Accessed September 13, 2021. 

Elsone L, Panicker J, Mutch K, et al. Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult Scler. 2014;20(4):501-4.

Eo TS, Chun KJ, Hong SJ, et al. Clinical Presentation, Management, and Prognostic Factors of Idiopathic Systemic Capillary Leak Syndrome: A Systematic Review. J Allergy Clin Immunol Pract. 2018 Mar - Apr;6(2):609-618.

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Fazekas F, Lublin FD, Li D, et al; PRIVIG Study Group; UBC MS/MRI Research Group. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis a dose-finding trial. Neurology. 2008;71(4) 265-71.

Feasby T, Banwell B, et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev. 2007;21(2 Suppl 1) S57-107.

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Sanchez-Ramon S, Dhalla F, Chapel H. Challenges in the role of gammaglobulin replacement therapy and vaccination strategies for hematological malignancy. Front. Immunol. 2016;7:317.

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Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher. 2016 Jun;31:149-62.

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Sinha AA, Hoffman MB, Janicke EC. Pemphigus vulgaris: approach to treatment. Eur J Dermatol. 2015;25(2):103-13.

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Sun D, Shehata N, Ye XY, et al. Corticosteroids compared with intravenous immunoglobulin for the treatment of immune thrombocytopenia in pregnancy. Blood. 2016;128:1329-1335.

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Svecova D. IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects. Australas J Dermatol. 2016;57:141-144.

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Tavakolpour S. The role of intravenous immunoglobulin in treatment of mucous membrane pemphigoid: A review of the literature. J Res Med Sci. 2016;21:37.

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Visentin A, Compagno N, Cinetto F, et al. Clinical profile associated with infections in patients with chronic lymphocytic leukemia. Protective role of immunoglobulin replacement therapy. Haematologica, 2015;100:e515-518.

Viswanathan S, Wong AHY, Quek AML, et al. Intravenous immunoglobulin may reduce relapse frequency in neuromyelitis optica. J Neuroimmunol. 2015;282:92-96.

Voto LS, Sexer H, Ferreiro G, et al. Neonatal administration of high-dose intravenous immunoglobulin in rhesus hemolytic disease. J Perinat Med. 1995;23(6) 443-51.

Vu D, Shah T, Ansari J, et al. Efficacy of intravenous immunoglobulin in the treatment of persistent BK viremia and BK virus nephropathy in renal transplant recipients. Transplant Proc. 2015;47:394-398.

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REFERENCES FOR EXPERIMENTAL/INVESTIGATIONAL INDICATIONS

Alzheimer's Disease

Amanatkar HR, Papagiannopoulos B, Grossberg GT. Analysis of recent failures of disease modifying therapies in Alzheimer’s disease suggesting a new methodology for future studies. Expert Rev Neurother. 2017;17:7-16.

Dodel R, Neff F, Noelker C, et al. Intravenous immunoglobulins as a treatment for Alzheimer's disease rationale and current evidence. Drugs. 2010;70(5) 513-28.

Dodel R, Rominger A, Bartenstein P, et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2013 Mar;12(3):233-43.

Kile S, Au W, Parise C, et al. IVIG treatment of mild cognitive impairment due to Alzheimer’s disease: a randomized double-blinded exploratory study of the effect on brain atrophy, cognition and conversion to dementia. J Neurol Neurosurg Psychiatry. 2017;88:106-112.

Liu J, Wang LN. Intravenous immunoglobulins for Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease: A systematic review with meta-analysis. Expert Rev Neurother. 2019 Jun;19(6):475-480.

Manolopoulos A, Andreadis P, Malandris K, et al. Intravenous Immunoglobulin for Patients With Alzheimer's Disease: A Systematic Review and Meta-Analysis. Am J Alzheimers Dis Other Demen. 2019 Aug;34(5):281-289.

Puli L, Tanila H, Relkin N. Intravenous immunoglobulins for Alzheimer's disease. Curr Alzheimer Res. 2014;11(7):626-36.

Relkin N. Intravenous immunoglobulin for Alzheimer's disease. Clin Exp Immunol. 2014 Dec;178 Suppl 1:27-9.

Relkin N, on behalf of the GAP Study Group. Results of GAP (160701): a Phase III study of intravenous gammaglobulin for the treatment of mild to moderate Alzheimer’s disease. Presented at AAIC, Boston 2013.

Relkin NR, Szabo P, Adamiak B, et al. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009 Nov;30(11):1728-36.

Relkin NR, Thomas RG, Rissman RA, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology. 2017;88:1768-1775.

Autism

Connery K, Tippett M, Delhey LM, et al. Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism. Transl Psychiatry. 2018 Aug 10;8(1):148.

DelGiudice-Asch G, Simon L, Schmeidler J, et al. J Autism Dev Disord. 1999;29 157-160.

Feasby T, Banwell B, Benstead T, et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev. 2007;21(Suppl 1) S57-S107.

Gupta S. Treatment of children with autism with intravenous immunoglobulin. J Child Neurol. 1999;14 203-205.

Kidd PM. Autism, an extreme challenge to integrative medicine. Part 2 medical management. Altern Med Rev. 2002;7 472-499.

Krause I, He XS, Gershwin ME, et al. Brief report immune factors in autism a critical review. J Autism Dev Discord. 2002;32 337-345.

Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383(9920):896-910. Epub 2013 Sep 26.

Plioplys AV. Intravenous immunoglobulin treatment of children with autism. J Child Neurol. 1998;13 79-82.

Plioplys AV. Response to the letter by Dr Gupta concerning the treatment of autistic children with intravenous immunoglobulin. J Child Neurol. 1999;14 203-205.

Robinson P, Anderson D, Brouwers M, et al; IVIG Hematology and Neurology Expert Panels. Evidence-based guidelines on the use of intravenous immune globulin for hematologic and neurologic conditions. Transfus Med Rev.2007;21(2 Suppl 1):S3-8.

Rossignol DA, Frye RE. A Systematic Review and Meta-Analysis of Immunoglobulin G Abnormalities and the Therapeutic Use of Intravenous Immunoglobulins (IVIG) in Autism Spectrum Disorder. J Pers Med. 2021 May 30;11(6):488. 

Weissman L, Harris HK. Autism spectrum disorders in children and adolescents: Complementary and alternative therapies. 02/05/2020. UpToDate Website. Available at: http://www.uptodate.com/contents/autism-spectrum-disorders-in-children-and-adolescents-complementary-and-alternative-therapies?source=search_result&search=seizures+AND+IVIG&selectedTitle=5~150. Accessed September 15, 2021.

Whitehouse AJ. Complementary and alternative medicine for autism spectrum disorders: rationale, safety and efficacy. J Paediatr Child Health. 2013 Sep;49(9):E438-42:quiz E442. Epub 2013 May 20.

Wong PH, White KM. Impact of immunoglobulin therapy in pediatric disease: A review of immune mechanisms. Clinic Rev Allerg Immunol. 2017;51:303-314.

Autoimmune Encephalopathy

Bartolini L, Muscal E. Differences in treatment of anti-NMDA receptor encephalitis: results of a worldwide survey. J Neurol. 2017 Apr;264(4):647-653.

Brenton JN, Goodkin HP. Antibody-mediated autoimmune encephalitis in childhood. Pediatr Neurol. 2016;60:13-23.

Byun JI, Lee ST, Jung KH, et al. Effect of Immunotherapy on Seizure Outcome in Patients with Autoimmune Encephalitis: A Prospective Observational Registry Study. PLoS One. 2016;11(1):e0146455.

Caselli RJ, Drazkowski JF, Wingerchuk DM. Autoimmune encephalopathy. Mayo Clin Proc. 2010;85(10):878-80.

Connery K, Tippett M, Delhey LM, et al. Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism. Transl Psychiatry. 2018 Aug 10;8(1):148.

Dale RC, Gorman MP, Lim M. Autoimmune encephalitis in children: clinician phenomenology, therapeutics, and emerging challenges. Curr Opin Neurol. 2017 Feb 22.

Dalmau J, Rosenfeld MR, et al. Paraneoplastic and autoimmune encephalitis. UpToDate Website. 09/27/2021. Available at: http://www.uptodate.com/contents/paraneoplastic-and-autoimmune-encephalitis?source=search_result&search=paraneoplastic+limbic+encephalitis&selectedTitle=1~2#H2380193. Accessed October 12, 2021.

Flanagan EP, Caselli RJ. Autoimmune encephalopathy. Semin Neurol. 2011;31 144-157.

Gastaldi M, Thouin A, Vincent A. Antibody-Mediated Autoimmune Encephalopathies and Immunotherapies. Neurotherapeutics. 2016;13(1):147-62.

Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016 Apr;15(4):391-404.

Kalman B. Autoimmune encephalitides: A broadening field of treatable conditions. Neurologist. 2017;22:1-13.e.

Lancaster E. The Diagnosis and Treatment of Autoimmune Encephalitis. J Clin Neurol. 2016;12(1):1-13.

Lazar-Molner E, Tebo AE. Autoimmune NMDA receptor encephalitis. Clinica Chimica Acta. 2015;438:90-97.

Nanri K, Okuma M, Sato S, et al. Prevalence of Autoantibodies and the Efficacy of Immunotherapy for Autoimmune Cerebellar Ataxia. Intern Med. 2016;55(5):449-54. Epub 2016 Mar 1.

Nosadini M, Mohammad SS, Ramanathan S, Brilot F, Dale RC. Immune therapy in autoimmune encephalitis: a systematic review. Expert Rev Neurother. 2015;15(12):1391-419.

Shin YW, Lee ST, Park KI, et al. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord. 2017 Aug 16;11:1756285617722347.

Suthar R, Saini AG, Sankhyan N, Sahu JK, Singhi P. Childhood Anti-NMDA Receptor Encephalitis. Indian J Pediatr. 2016 Jul;83(7):628-33.

Titulaer M, McCracken L, Cuellar IG, et al. Clinical Features, Treatment, and Outcome of 500 Patients with Anti-NMDA Receptor Encephalitis (PL01.001). Neurology Apr 2012, 78 (1 Supplement) PL01.001.

Hemolytic uremic syndrome

Benamu E, Montoya JG. Infections associated with the use of eculizumab: recommendations for prevention and prophylaxis. Curr Opin Infect Dis. 2016 Aug;29(4):319-29.

Khandelwal P, Gupta A, Sinha A, et al. Effect of plasma exchange and immunosuppressive medications on antibody titers and outcome in anti-complement factor H antibody-associated hemolytic uremic syndrome. Pediatr Nephrol. 2015;30:451-457.

Legendre CM, Campistol JM, Feldkamp T, et al. Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis. Transpl Int. 2017 Dec;30(12):1275-1283.

Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016;31:15-39.

Mayo Clinic. Hemolytic uremic syndrome. 07/22/2021. Available at: http://www.mayoclinic.org/diseases-conditions/hemolytic-uremic-syndrome/diagnosis-treatment/treatment/txc-20204170. Accessed September 15, 2021.​

National Organization for Rare Diseases. Atypical uremic syndrome. 2016. Available at: https://rarediseases.org/rare-diseases/atypical-hemolytic-uremic-syndrome/. Accessed September 15, 2021.​

Niaudet P. Boyer OG. Compliment-mediated hemolytic mediated hemolytic uremic syndrome in children. 08/30/2021. UpToDate Website. Available at: https://www.uptodate.com/contents/complement-mediated-hemolytic-uremic-syndrome?source=search_result&search=hemolytic uremic syndrome&selectedTitle=2~150. Accessed September 15, 2021.​

Niaudet P, Boyer OG. Overview of hemolytic uremic syndrome in children. 04/22/2021. UpToDate Website. Available at: https://www.uptodate.com/contents/overview-of-hemolytic-uremic-syndrome-in-children?source=search_result&search=HUS&selectedTitle=1~150. Accessed September 15, 2021.​

Parmar MS. Hemolytic-uremic syndrome treatment and management. Medscape Website. 07/02/2021. Available at: http://emedicine.medscape.com/article/201181-treatment. Accessed September 15, 2021.​

Taylor CM, Machin S, Wigmore SJ, et al. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol. 2010;148:37-47.

Truven Health Analytics Inc. Micromedex® Solutions. DrugDex®. [Internet database]. Immune Globulin. 08/31/2021. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ [via subscription only]. Accessed September 15, 2021.​

Watt T, Warshaw B, Katzenstein HM. Atypical hemolytic uremic syndrome responsive to steroids and intravenous immune globulin. Pediatr Blood Cancer. 2009 Jul;53(1):90-1.

Multiple sclerosis: Primary Progressive or Secondary Progressive

Filippini G, Del Giovane C, Vacchi L, et al. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2013;(6):CD008933.

Olek MJ, Mowry E. Treatment of secondary progressive multiple sclerosis in adults. 04/26/2021. UpToDate Website. Available at: https://www.uptodate.com/contents/treatment-of-progressive-multiple-sclerosis-in-adults?source=search_result&search=multiple sclerosis&selectedTitle=5~150. Accessed November 3, 2021. 

Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of the evidence. J Allergy Clin Immunol. 2017;139:S1-S45.

Myocarditis (Acute)

Allan CK, Fulton DR. Treatment and prognosis of myocarditis in children. UpToDate Website. 08/26/2021. Available at: https://www.uptodate.com/contents/treatment-and-prognosis-of-myocarditis-in-children?source=search_result&search=myocarditis&selectedTitle=5~150. Accessed October 27, 2021.

Butts RJ, Boyle GJ, Deshpande SR, et al. Characteristics of Clinically Diagnosed Pediatric Myocarditis in a Contemporary Multi-Center Cohort. Pediatr Cardiol. 2017 Aug;38(6):1175-1182.

Cooper LT. Treatment and prognosis of myocarditis in adults. UpToDate Website. 06/17/2020. Available at: https://www.uptodate.com/contents/treatment-and-prognosis-of-myocarditis-in-adults?source=search_result&search=myocarditis&selectedTitle=2~150. Accessed October 27, 2021.​

Donovan S, Bearman GML. Use of intravenous immunoglobulin in critically ill patients. Curr Infect Dis Rep. 16:447.

Drucker NA, Colan SD, Lewis AB, et al. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation. 1994;89:252-257.

English RF, Janosky JE, Ettedqui JA, et al. Outcomes for children with acute myocarditis. Cardiol Young. 2004;14:488-493.

Ghelani SJ, Spaeder MC, Pastor W, et al. Demographics, trends and outcomes in pediatric acute myocarditis in the United States, 2006 to 2011. Circ Cardiovasc Qual Outcomes. 2012;5:622-627.

Gullestad L, Aass H, Fjeld JG, et al. Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation. 2001;103:220-225.

Haque A, Bhatti S, Siddiqui FJ. Intravenous immune globulin for severe acute myocarditis in children. Indian Pediatr. 2009;46:810-811.

Huang X, Sun Y, Su G, Li Y, Shuai X. Intravenous Immunoglobulin Therapy for Acute Myocarditis in Children and Adults. Int Heart J. 2019 Mar 20;60(2):359-365.

Hufnagel G, Pankuweit S, Richter A, Schönian U, Maisch B. The European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID). First epidemiological results. Herz. 2000 May;25(3):279-85.

Kim HJ, Yoo GH, Kil HR. Clinical outcome of acute myocarditis in children according to treatment modalities. Korean J Pediatr. 2010;53:745-752.

Kindermann I, Barth C, Mahfoud F, et al. Update on myocarditis. J Am Coll Cardiol. 2012;59:779-792.

Kishimoto C, Shioji K, Hashimoto T, et al. Therapy with immunoglobulin in patients with acute myocarditis and cardiomyopathy. Analysis of leukocyte balance. Heart Vessels. 2014;29:336-342.

Klugman D, Berger JT, Sable C’A, et al. Pediatric patients hospitalized with myocarditis: a multi-institutional analysis. Pediatr Cardiol. 2010;31:222-228.

Lee KJ, McCrindle DJ, Bohn GJ, et al. Clinical outcomes of acute myocarditis in childhood. Heart. 1999;82:226-233.

Mansourabadi AH, Gol Mohammad Pour Afrakoti L, Shahi A, Shabanian R, Amirzargar A. Intravenous Immunoglobulin Therapy in Myocarditis. Iran J Allergy Asthma Immunol. 2020 Aug 25;19(4):323-336. 

McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation. 2001;103:2254-2259.

Prasad AN, Chaudhary S. Intravenous immunoglobulin in children with acute myocarditis and/or early dilated cardiomyopathy. Indian Pediatr. 2014;51:583-584.

Robinson J, Hartling L, Vandermeer B, et al. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. 2015 May 20; (5): CD004370.

Robinson J, Hartling L, Vandermeer B, Sebastiansk​i M, Klassen TP. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. 2020 Aug 19;8(8):CD004370.
Neonatal sepsis treatment

Edwards MS. Management and outcome of sepsis in term and late preterm infants. UpToDate Website. 04/30/2021. Available at: https://www.uptodate.com/contents/management-and-outcome-of-sepsis-in-term-and-late-preterm-infants?source=search_result&search=neonatal sepsis&selectedTitle=2~91. Accessed October 29, 2021.​

Fleisher TA. Treatment of neonatal sepsis with immune globulin. Pediatrics. 2012:130(1).

Gollehon NS. Neonatal sepsis treatment and management. Medscape. 06/13/19. Available at: http://emedicine.medscape.com/article/978352-treatment#d8. Accessed October 29, 2021.​

INIS Collaborative Group. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med. 2011;365:1201-1211.

Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev. 2015 Mar 27; (3):CD01239.

Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev. 2020 Jan 29; (3):CD01239.

Pammi M. Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation. 04/30/20210. Available at: https://www.uptodate.com/contents/treatment-and-prevention-of-bacterial-sepsis-in-preterm-infants-less-than34-weeks-gestation?search=bacterial sepsis in preterm&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed October 29, 2021.

Wong PH, White KM. Impact of immunoglobulin therapy in pediatric disease: A review of immune mechanisms. Clinic Rev Allerg Immunol. 2017;51:303-314.

Paraneoplastic Limbic Encephalitis

Blaes F, Strittmatter M, Merkelbach S, et al. Intravenous immunoglobulins in the therapy of paraneoplastic neurological disorders. J Neurol. 1999;246 299-203.

Dalmau J, Rosenfeld MR, et al. Paraneoplastic and autoimmune encephalitis. UpToDate Website. 09/27/2021. Available at: http://www.uptodate.com/contents/paraneoplastic-and-autoimmune-encephalitis?source=search_result&search=paraneoplastic+limbic+encephalitis&selectedTitle=1~2#H2380193. Accessed October 12, 2021.​

Derry CP, Wilkie MD, Al-Shahi S, et al. Autoimmune limbic encephalitis. Clin Med. 2011;11 476-478.

Flanagan EP, Drubach DA, Boeve BF. Autoimmune dementia and encephalopathy. Handb Clin Neurol. 2016;133:247-267.

Grisold W, Giometto B, Vitaliani R, et al. Current approaches to the treatment of paraneoplastic encephalitis. Ther Adv Neurol Disord. 2011;4 237-248.

Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis analysis of 200 patients. Brain. 2001;124 1138-1148.

Keime-Guibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry. 2000;68 479-482.

NIH. GARD Genetic & Rare Diseases Information Center. Limbic encephalitis. 2016. Available at: https://rarediseases.info.nih.gov/diseases/8742/limbic-encephalitis. Accessed October 12, 2021. 

Uchuya M, Graus F, Verg F, et al. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry. 1996;60 388-392.

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS)

Alexander AA, Patel NJ, Southammakosane CA, Mortensen MM. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): an indication for tonsillectomy. Int J Pediatr Otorhinolaryngol. 2011;75(6):872-3. 

American Academy of Allergy, Asthma and Immunology. Position statement on the appropriate use of intravenously administered immunoglobulin (IGIV). January 2005. 

Chiarello F, Spitoni S, Hollander E, et al. An expert opinion on PANDAS/PANS: highlights and controversies. Int J Psychiatry Clin Pract. 2017;21:91-98.

Farhood Z, Ong AA, Discolo CM. PANDAS: A systematic review of treatment options. Int J Pediatr Otorhinolaryngol. 2016;89:149-53.

Frankovich J, Swedo SE, Murphy TK, et al. Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II—Use of Immunomodulatory Therapies. Journal of Child and Adolescent Psychopharmacology. 2017;27(7):1-16.

Gause C, Morris C, Vernekar S, Pardo-Villamizar C, Grados MA, Singer HS. Antineuronal antibodies in OCD: comparisons in children with OCD-only, OCD+chronic tics and OCD+PANDAS. J Neuroimmunol. 2009;214(1-2):118-24. Epub 2009 Jul 22.

Gilbert DL, Kurlan R. PANDAS: horse or zebra? Neurology. 2009;73(16):1252-3.

Hoekstra PJ, Minderaa RB, Kallenberg CG. Lack of effect of intravenous immunoglobulins on tics a double-blind placebo-controlled study. J Clin Psychiatry. 2004;65 537-542.

Kurlan R, Kaplan EL. The pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms Hypothesis or entity? Practical considerations for the clinician. Pediatrics. 2004;113 883-886.

Lechman JF, King RA, Gilbert DL, et al. Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms A prospective longitudinal study. J Am Acad Child Adolesc Psychiatry. 2011;50 108-118.

Leonard HL, Swedo SE. Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Int J Neuropsychopharmacol. 2001;4 191-198.

Lewin AB, Storch EA, Murphy TK. Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus in identical siblings. J Child Adolesc Psychopharmacol. 2011;21(2):177-82.

Kovacevic M, Grant P, Swedo SE. Use of intravenous immunoglobulin in the treatment of twelve youths with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Child Adolesc Psychopharmacol. 2015 Feb;25(1):65-9.

Macerollo A, Martino D. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): An Evolving Concept. Tremor Other Hyperkinet Mov (N Y). 2013;3. pii: tre-03-167-4158-7. eCollection 2013.

Martino D, Defazio G, Giovannoni G. The PANDAS subgroup of tic disorders and childhood-onset obsessive-compulsive disorder. J Psychosom Res. 2009;67 547-557

Moretti G, Pasquini M, Mandarelli G, et al. What every psychiatrist should know about PANDAS a review. Clin Pract Epidemiol Ment Health. 2008;4 13.

Morris CM, Pardo-Villamizar C, Grause CD, et al. Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls. J Neurol Sci. 2009;276(1-2) 45-8.

Murphy TK, Gerardi DM, Leckman JF. Pediatric acute-onset neuropsychiatric syndrome. Psychiatr Clin North Am. 2014;37(3):353-74. Review.

Murphy TK, Kurlan R, Leckman J. The immunobiology of Tourette’s disorder, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus, and related disorders A way forward. J Child Adolesc Psychopharmacol. 2010;20 317-331.

National Institute of Mental Health. PANDAS: Frequently asked questions about Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. 2019. Available at: https://www.nimh.nih.gov/health/publications/pandas/index.shtml#pub3. Accessed October 27, 2021.

Nicolson R, Swedo SE, Lenane M, et al. An open trial of plasma exchange in childhood-onset obsessive-compulsive disorder without poststreptococcal exacerbations. J Am Acad Child Adolesc Psychiatry. 2000; 39:1313.

Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of the evidence. J Allergy Clin Immunol. 2017;139:S1-S45.

Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999;354 1153-1158.

Pichichero ME. PANDAS: Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci. 06/04/2021. UpToDate Website. Available at: https://www.uptodate.com/contents/pandas-pediatric-autoimmune-neuropsychiatric-disorder-associated-with-group-a-streptococci?source=search_result&search=PANDAs&selectedTitle=1~10. Accessed October 27, 2021.

Practice parameter for the assessment and treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 2012 Jan;51(1):98-113.

Provon D, Nokes TJC, Agrawal S, et al. Clinical guidelines for immunoglobulin use. 2nd edition. May 30, 2008. UK Dept of Health.

Robinson P, Anderson D, Brouwers M, et al.; IVIG Hematology and Neurology Expert Panels. Evidence-based guidelines on the use of intravenous immune globulin for hematologic and neurologic conditions. Transfus Med Rev. 2007;21(2 Suppl 1):S3-8.

Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher. 2013;28(3):145-284.

Shulman ST. Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS): update. Curr Opin Pediatr. 2009;21(1):127-30.

Sigra S, Hesselmark E, Bejerot S. Treatment of PANDAS and PANS: a systematic review. Neurosci Biobehav Rev. 2018 Mar;86:51-65.

Swedo SE, Lechman JF, Rose NR. From research subgroup to clinical syndrome Modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Pediatr Therapeut. 2012;2 ISSN 2161-0665.

Swedo SE, Leonard HL, Garvey M, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections clinical description of the first 50 cases. Am J Psychiatry. 1998;155 264-271.

Swedo SE, Leonard HL, Rapoport JL. The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction. Pediatrics. 2004;113(4):907.

Tan J, Smith CH, Goldman RD. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Can Fam Physician. 2012;58(9):957-9.

Williams KA, Swedo SE, Farmer CA, et al. Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections. J Am Acad Child Adolesc Psychiatry. 2016;55(10):860-867.e2.

Wong PH, White KM. Impact of immunoglobulin therapy in pediatric disease: A review of immune mechanisms. Clinic Rev Allerg Immunol. 2017;51:303-314.

Pericarditis Refractory, Recurrent

Alder Y, Charron P, Imazio M, et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases. Eur Heart J. 2015;36:2921-2964.

Baskar S. Pediatric pericarditis. American College of Cardiology Website. 06/08/16. 

Brown A, Kontzias A. The evolving relationship of cardiology and rheumatology in treating patients with recurrent pericarditis. American College of Cardiology Website. Oct 12, 2016. 

Cremer PC, Kumar A, Kontzias A, et al. Complicated pericarditis: Understanding risk factors and pathophysiology to inform imaging and treatment. J Am Coll Cardiol. 2016;68:2311-2328.

Dauphin C, Merlin E, Chalard A, et al. Recurrent pericarditis: current challenges and future prospects. Research Reports in Clinical Cardiology. 2016:7:99-108.

Del Fresno MR, Peralta JE, Granados MA, et al. Intravenous immunoglobulin therapy for refractory recurrent pericarditis. Pediatrics. 2014;134:1441-1446.

Galluzzo A, Imazio M. Advances in medical therapy for pericardial diseases. Expert Rev Cardiovasc Ther. 2018 Sep;16(9):635-643.

Imazio M, Adler Y, Charron P. Recurrent pericarditis: Modern approach in 2016. Curr Cardiol Rep. 2016;18:50-59.

Imazio M, Gaita F. Acute and Recurrent Pericarditis. Cardiol Clin. 2017 Nov;35(4):505-513.

Imazio M, Lazaros G, Picardi E, et al. Intravenous human immunoglobulins for refractory recurrent pericarditis: a systematic review of all published cases. J Cardiovasc Med. 2016;17:263-269.

Lotan D, Wasserstrum Y, Fardman A, et al. Usefulness of novel immunotherapeutic strategies for idiopathic recurrent pericarditis. Am J Cardiol. 2016;117:861-866.

Mookadam F. Pericardial diseases guidelines: Coming of age and making sense with evidence in the field of pericardiology. American College of Cardiology. 11/17/15. 

Moretti M, Buiatti A, Merlo M, et al. Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis. Am J Cardiol. 2013;112:1493-1498.

Peterlana D, Puccetti A, Simeoni S, et al. Efficacy of intravenous immunoglobulin in chronic idiopathic pericarditis: report of 4 cases. Clin Rheumatol. 2005;24:18-21.

Schwier NC, Hale GM, Davies ML. Treatment of Adults with Idiopathic Recurrent Pericarditis: Novel Use of Immunotherapy. Pharmacotherapy. 2017 Mar;37(3):305-318.

Tousoulis D. Incessant and recurrent pericarditis: Corticosteroids or novel immune-suppressants agents. Hellenic J Cardiol. 2019 Nov-Dec;60(6):345-346. 
Peripheral Neuropathy of Unknown Etiology with Peroneal Muscle Atrophy

Donofrio PD, Berger A, Brannagan TH, et al. Consensus Statement the use of intravenous immunoglobulin in the treatment of neuromuscular conditions report of the AANEM Ad Hoc Committee. Muscle Nerve. 2009;40 890-900.

Elovaara I, Apostolski S, van Doorn P, et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurol. 2008;15 893-908.

Ginsberg L, Malik O, Kenton AR, et al. Coexistent hereditary and inflammatory neuropathy. Brain. 2004;127 193-202.

Kang PB. Charcot-Marie-Tooth disease: Management and prognosis. 02/03/2020. Available at: https://www.uptodate.com/contents/charcot-marie-tooth-disease-management-and-prognosis?search=Charcot-Marie-Tooth&source=search_result&selectedTitle=2~53&usage_type=default&display_rank=2#H814764001. Accessed November 3, 2021. ​

National Institute of Neurological Disorders and Stroke. Charcot-Marie-Tooth disease fact sheet. 06/08/2020. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Charcot-Marie-Tooth-Disease-Fact-Sheet#3092_6. Accessed November 3, 2021.​

Schenone A, Nobbio L, Monti BM, et al. Inherited neuropathies. Curr Treat Options Neurol. 2011;13 160-179.

The Charcot-Marie-Tooth Association. What is CMT? Available at: https://www.cmtausa.org/understanding-cmt/what-is-cmt/. Accessed November 3, 2021.

Postural Tachycardia Syndrome (POTS)

Cheshire WP. Postural tachycardia syndrome. Up-To-Date Website. Updated 03/12/2021. Available at: http://www.uptodate.com/contents/postural-tachycardia-syndrome. Accessed November 3, 2021.​

 Grubb BP. Postural tachycardia syndrome. Circulation. 2008;117(21) 2814-7.

Low PA, Sandroni P, Joyner M, et al. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol. 2009;20 352-358.

NINDS Postural Tachycardia Syndrome Information Page. National Institute of Neurological Disorders and Stroke. Updated 03/2019. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Postural-Tachycardia-Syndrome-Information-Page. Accessed November 3, 2021.

Yellow Nail Syndrome

Gupta S, Samra D, Yel L, Agrawal S. T and B cell deficiency associated with yellow nail syndrome. Scand J Immunol. 2012;75(3) 329-35.

Kurin M, Wiesen J, Mehta AC. Yellow nail syndrome: a case report and review of treatment options. Clin Respir J. 2017;11:405-410.

Maldonado F, Tazelaar HD, Wang CW, Ryu JH. Yellow nail syndrome analysis of 41 consecutive patients. Chest. 2008;134(2) 375-81.

Maldonado F, Ryu JH. Yellow nail syndrome. Curr Opin Pulm Med. 2009;15(4) 371-5.

National Association for Rare Disorders. Yellow nail syndrome. 2018. Available at: https://rarediseases.org/rare-diseases/yellow-nail-syndrome/. Accessed September 15, 2021.

Vignes S, Baran R. Yellow nail syndrome: A review. Orphanet J Rare Dis. 2017;12:42.

Zarogiannis S, Hatzoglou C, Molyvdas P-A, Gourgoulianis K. Yellow nail syndrome chylous pleural effusions defective lymph valves involved. Chest. 2008;134(6) 1353.​

Coding

CPT Procedure Code Number(s)
N/A
ICD - 10 Procedure Code Number(s)
N/A
ICD - 10 Diagnosis Code Number(s)
See Attachment B.
HCPCS Level II Code Number(s)
MEDICALLY NECESSARY

SUBCUTANEOUS IMMUNE GLOBULIN (SCIG)
J1555Injection, immune globulin (cuvitru), 100 mg
J1558Injection, immune globulin (xembify), 100 mg
J1559Injection, immune globulin (Hizentra), 100 mg
J1561Injection, immune globulin, (Gamunex/Gamunex-C/Gammaked), nonlyophilized (e.g., liquid), 500 mg
J1569Injection, immune globulin, (Gammagard liquid), nonlyophilized, (e.g., liquid), 500 mg

The following code is used to represent HyQvia:
J1575 Injection, immune globulin/hyaluronidase, 100 mg immuneglobulin

The following code are used to represent Cutaquig: 
J1551Injection, immune globulin (cutaquig), 100 mg​

INTRAVENOUS IMMUNE GLOBULIN (IVIG)
J1459 Injection, immune globulin (Privigen), intravenous, non-lyophilized (e.g. liquid), 500 mg
J1554
Injection, immune globulin (asceniv), 500 mg​
J1556Injection, immune globulin (bivigam), 500 mg
J1557Injection, immune globulin (Gammaplex), intravenous, non-lyophilized (e.g. liquid), 500 mg
J1561 Injection, immune globulin, (Gamunex​/Gamunex-C/Gammaked), non-lyophilized (e.g. liquid), 500 mg
J1568
Injection, immune globulin, (Octagam), intravenous, non-lyophilized (e.g. liquid), 500 mg
J1569Injection, immune globulin, (Gammagard liquid), intravenous, non-lyophilized, (e.g. liquid), 500 mg
J1572Injection, immune globulin, (Flebogamma/Flebogamma Dif), intravenous, non-lyophilized (e.g. liquid), 500 mg
​J1576

Injection, immune globulin (panzyga), intravenous, non-lyophilized (e.g. liquid), 500 mg​

​Q2052
​Services, supplies and accessories used in the home for the administration of intravenous immune globulin (ivig)​
S9338 Home infusion therapy, immunotherapy, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem

The following code is used to represent GAMMAGARD S/D:
J1566 Injection, immune globulin, intravenous, lyophilized (e.g. powder), not otherwise specified, 500 mg

NOT ELIGIBLE FOR REIMBURSEMENT ​

THE FOLLOWING CODE REPRESENTS VIVAGLOBIN WHICH IS NO LONGER MANUFACTURED AND HAS BEEN WITHDRAWN FROM THE MARKET:
J1562 Injection, immune globulin (Vivaglobin), 100 mg


THE FOLLOWING CODE REPRESENTS CARIMUNE NF WHICH IS NO LONGER MANUFACTURED AND HAS BEEN WITHDRAWN FROM THE MARKET:

J1566 Injection, immune globulin, intravenous, lyophilized (e.g. powder), not otherwise specified, 500 mg​

Revenue Code Number(s)
N/A

​

​

Coding and Billing Requirements

Policy History

Revisions From 08.00.13ah:
01/01/2024

This version of the policy will become effective 01/01/2024.


The following HCPCS code has been added to this policy:
Q2052 Services, supplies and accessories used in the home for the administration of intravenous immune globulin (ivig)

Revisions From 08.00.13ag:
10/01/2023

This version of the policy will become effective 10/01/2023.


The following ICD-10 CM codes have been added to this policy:

G40.C11 Lafora progressive myoclonus epilepsy, intractable, with status epilepticus

G40.C19 Lafora progressive myoclonus epilepsy, intractable, without status epilepticus​


Revisions From 08.00.13af:
07/01/2023

This version of the policy will become effective 07/01/2023.


The following NOC code has been removed from this policy and is replaced by the following HCPCS code:
  • Removed: J1599 Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500mg
  • Replaced With: J1576 Injection, immune globulin (panzyga), intravenous, non-lyophilized (e.g., liquid), 500 mg

Revisions From ​08.00.13ae:
10/01/2022

This version of the policy will become effective 10/01/2022.

​
The following ICD-10 CM code has been termed (no longer valid codes) and removed from this policy for IVIG:
D68.0 Von Willebrand's disease

The following ICD-10 CM codes have been added to this policy for IVIG:
D68.00 Von Willebrand disease, unspecified
D68.01 Von Willebrand disease, type 1
D68.020 Von Willebrand disease, type 2A
D68.021 Von Willebrand disease, type 2B
D68.022 Von Willebrand disease, type 2M
D68.023 Von Willebrand disease, type 2N
D68.029 Von Willebrand disease, type 2, unspecified
D68.03 Von Willebrand disease, type 3
D68.04 Acquired von Willebrand disease
D68.09 Other von Willebrand disease
I77.82 Antineutrophilic cytoplasmic antibody [ANCA] vasculitis

The following ICD-10 CM code has been added to this policy for IVIG and SCIG: 
D81.82 Activated Phosphoinositide 3-kinase Delta Syndrome (APDS)​​​

Revisions From ​08.00.13ad:
07/01/2022

This policy has been identified for the HCPCS code update, effective 07/01/2022.


The following NOC codes have been removed from this policy and are replaced by the following HCPCS code:
REMOVED: 
C9399 Unclassified drugs or biologicals
J7799 NOC drugs, other than inhalation drugs, administered through DME
REPLACED WITH: 
J1551 Injection, immune glo​bulin (cutaquig), 100 mg ​

Revisions From ​08.00.13ac:
01/31/2022

This version of the policy will become effective 01/31/2022.


This policy has been updated to communicate the coverage position for the following:

  • Claims for Carimune NF are not eligible for reimbursement, since it was withdrawn from the market. The HCPCS code will remain set up as eligible, since it also represents GAMMAGARD S/D​. (J1566 Injection, immune globulin, intravenous, lyophilized (e.g. powder), not otherwise specified, 500 mg​)​
  • National Comprehensive Cancer Network (NCCN)
    • NCCN Clinical Practice Guidelines in Oncology - Management of immune checkpoint inhibitor-related toxicities. V.3.2021. 05/14/2021. 
    • NCCN Drugs & Biologics Compendium. Immune globulin. [NCCN Web site]. 2021. Accessed September 1, 2021.​
      • Acquired (secondary) hypogammaglobulinemia in oncologic conditions
      • Management of ​Immune checkpoint inhibitor-related toxicities
  • Transplant: Clarification has been added for Solid organ transplant amongst sensitized transplant candidates​.
  • NMO: expanded prior therapy options.  
  • HIV-infected individuals to reduce baterial infection: timeframe of dosing expanded from every 28 days to every 2-4 weeks. 
  • CIDP Dosing & Frequency updated in alignment with Hizentra FDA labeling
The following ICD-10 CM code has been termed (no longer valid code) from this policy for SCIG, and has replaced by the following codes:
​Termed: 
D84.8 Other specified immunodeficiencies 
Added:
D84.81 Immunodeficiency due to conditions classified elsewhere
D84.821 Immunodeficiency due to drugs
D84.822 Immunodeficiency due to external causes
D84.89 Other immunodeficiencies

The following ICD-10 CM codes have been added to this policy for IVIG as Medically Necessary:
G04.89 Other myelitis
G04.90 Encephalitis and encephalomyelitis, unspecified
G04.91 Myelitis, unspecified
G37.3 Acute transverse myelitis in demyelinating disease of central nervous system
L13.9  Bullous disorder, unspecified
M60.80 - M60.89 Other myositis
M60.9   Myositis, unspecified
T80.90XA Unspecified complication following infusion and therapeutic injection, initial encounter 
T80.90XD Unspecified complication following infusion and therapeutic injection, subsequent encounter
T80.90XS Unspecified complication following infusion and therapeutic injection, sequela 

The following ICD-10 CM code for IVIG has been corrected for an error in the code nummber:
  • FROM: G25.8 Stiff-man syndrome 
  • TO: ​G25.82 Stiff-man syndrome
The following HCPCS codes have been corrected for errors in the narrative:
J1561 Injection, immune globulin, (Gamunex/Gamunex-C/Gammaked), non-lyophilized (e.g. liquid), 500 mg
J1569 Injection, immune globulin, (Gammagard liquid), intravenous, non-lyophilized, (e.g. liquid), 500 mg

Revisions From ​08.00.13ab:
04/01/2021

This policy has been identified for the HCPCS code update, effective 04/01/2021.


The following HCPCS code has been termed (no longer valid code) from this policy:

C9072 Injection, immune globulin (asceniv), 500 mg


The following HCPCS code has been removed from this policy to represent Asceniv (but will remain in the policy to represent Panzyga):​

J1599 Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500mg 


The following ICD-10 CM code has been added to this policy:

J1554 Injection, immune globulin (asceniv), 500 mg


Revisions From ​08.00.13aa:
01/01/2021

This policy has been identified for the HCPCS code update, effective 01/01/2021.


The following ICD-10 CM code has been added to this policy:

C9072 Injection, immune globulin (asceniv), 500 mg​


Revisions From 08.00.13z:
10/12/2020This version of the policy will become effective 10/12/2020​.

HCPCS "J3590 Unclassified biologics" has been replaced with "J7799 NOC drugs, other than inhalation drugs, administered through DME​" to represent Cutaquig. This is in alignment with Billing Requirements for Medicare contractor, Noridian Healthcare Solutions​​. 

Revisions From 08.00.13y:
10/01/2020This policy has been identified for the ICD-10 CM code update, effective 10/01/2020.

The following ICD-10 CM codes have been deleted for IVIG:

D59.1 Other autoimmune hemolytic anemias

D84.8 Other specified immunodeficiencies

 

The following ICD-10 CM code​s have been added for IVIG:

D59.10 Autoimmune hemolytic anemia, unspecified

D59.11 Warm autoimmune hemolytic anemia

D59.12 Cold autoimmune hemolytic anemia

D59.13  Mixed type autoimmune hemolytic anemia

D59.19 Other autoimmune hemolytic anemia

D84.81 Immunodeficiency due to conditions classified elsewhere

D84.89 Other immunodeficiencies

D84.821 Immunodeficiency due to drugs

D84.822 Immunodeficiency due to external causes 

​
Revisions From 08.00.13x:
07/20/2020This version of the policy will become effective 07/20/2020.

This policy was updated to communicate the following changes:
  • The addition of the following Indication and Dosing and Frequency Requirement for "Immune checkpoint inhibitor-related toxicities, management", in accordance with National Comprehensive Cancer Network (NCCN).
  • The removal of the following indications:
    • Benign mucous membrane pemphigoid, with or without mention of ocular movement, in accordance with CMS’ NCD 250.3.
    • Erythema multiforme major, due to terminology change. ICD-10 code was removed: L51.9 Erythema multiforme, unspecified
  • The criteria of "serious, recurrent bacterial infection" was added to the indication for acquired hypogammaglobulinemia due to CAR-T therapy.
  • Additional dosing regimen was added for anemia due to parvovirus B19 infection.
  • The following ICD-10 CM codes have been added for SCIG and IVIG:
      D84.8 Other specified immunodeficiencies
      D84.9 Immunodeficiency, unspecified
  • The following ICD-10 CM code has been added to this policy for IVIG:
      D68.4 Acquired coagulation factor deficiency

Revisions From 08.00.13w:
07/01/2020This policy has been identified for the HCPCS code update, effective 07/01/2020.

The following NOC codes have been removed from this policy for Xembify and are replaced by the following HCPCS code:

REMOVED:
C9399 Unclassified drugs or biologicals
J3590 Unclassified biologics

REPLACED WITH:
J1558 Injection, immune globulin (xembify), 100 mg

Revisions From 08.00.13v:
10/21/2019This policy was updated to communicate the Company's coverage criteria, including Dosing and Frequency, of the new SCIG product, Xembify. Two additional examples of Primary immunodeficiency diseases were added for IVIG and SCIG: Transient hypogammaglobulinemia of infancy and Purine nucleoside phosphorylase (PNP) deficiency. The indication of "Acquired (secondary) hypogammaglobulinemia in oncologic conditions" has been expanded to include "Other malignant diseases with associated hypogammaglobulinemia in an individual who has a high risk of serious, recurrent bacterial infections."

Revisions From 08.00.13u:
06/17/2019This Policy was revised with the following changes:
  • The following new SCIG product was added: Cutaquig
  • The following new IVIG products were added: AscenivTM, Panzyga®.
  • New FDA-approved indication for SCIG (e.g., Hizentra®) for CIDP was added.
  • Scleromyxedema – Changed to first-line therapy
  • New indication for IVIG, per Novitas L35093, for Systemic Capillary Leak Syndrome (SCLS) or Clarkson's Disease: IVIG is considered medically necessary and, therefore, covered in individuals with Systemic Capillary Leak Syndrome (SCLS) or Clarkson's Disease when associated with monoclonal gammopathy and used for prophylaxis to increase survival
  • New indication for IVIG: Chimeric antigen receptor (CAR) T cell therapy (e.g., tisagenlecleucel [Kymriah™], axicabtagene ciloleucel [Yescarta™]) acquired hypogammaglobulinemia when the individual has an IgG level of less than 600 mg/dL.
  • Criteria changes for Preterm and/or low-birth-weight neonates with severe hypogammaglobulinemia
  • Intractable seizures and epilepsies in infants: expanded coverage to children
  • Lambert-Eaton: plasma exchange was added an as example of prior therapies.
  • Neuromyelitis Optica (NMO) (Devic’s Syndrome): Removed plasma exchange as an example of a prior therapy. Added azathioprine as an example of a prior therapy.
  • NOT MEDICALLY NECESSARY USES FOR SCIG: clarification that this statement is for the treatment of PIDD only, not CIDP.
Hemolytic uremic syndrome coverage changed from Medically Necessary to Experimental/Investigational.

The following indications were added to the Experimental/Investigational Coverage Section:
  • Multiple sclerosis: Primary Progressive or Secondary Progressive
  • Myocarditis (Acute)
  • Neonatal sepsis treatment
  • Pediatric Acute-onset Neuropsychiatric Syndrome (PANS)
  • Pericarditis refractory, recurrent
The following CPT codes were removed from the policy: 90283, 90284

Attachment B: Dosage and Frequency
SCIG Section:
PIDD Induction dosing was expanded from 100-150mg/kg/weekly to 100-200mg/kg/weekly.
PIDD: Cutaquig dosing was added.
CIDP: New Indication. Hizentra dosing was added.

IVIG Section:
Dosing and Frequency were added/adjusted for the following IVIG indications:
  • Scleromyxedema
  • Systemic Capillary Leak Syndrome (SCLS) or Clarkson's Disease
  • Chimeric antigen receptor (CAR) T cell therapy
  • Antibody-Mediated Rejection (AMR)
  • Autoimmune neutropenia
  • Guillain-Barre syndrome
  • Myasthenia gravis syndrome
  • Neuromyelitis Optica (NMO) (Devic’s Syndrome)

Revisions From 08.00.13t:
01/01/2018This policy has been identified for the HCPCS code update, effective 01/01/2018.

The following NOC code has been removed from this policy and is replaced by the following HCPCS code: 


 REMOVED: J3590 Unclassified biologics
REPLACED WITH: J1555 Injection, immune globulin (cuvitru), 100 mg


Effective 10/05/2017 this policy has been updated to the new policy template format.​
1/1/2024
1/2/2024
08.00.13
Medical Policy Bulletin
Commercial
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No