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

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 intravenous immune globulin (IVIG) and subcutaneous immune globulin (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 and Not Medically Necessary below must also be reviewed.)​

SUBCUTANEOUS IMMUNE GLOBULIN (SCIG)
Immunodeficiency Syndromes

  • Hyperimmunoglobulinemia E syndrome (HIES) (Hyper-IgE syndromes, Job 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) 
  • Evans syndrome ​
  • 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 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 granulomatosis, MPA, Churg-Strauss syndrome):
  • Autoimmune neutropenia
  • Bone marrow transplantation 
  • CAPS
  • Coagulopathy due to acquired inhibitor of clotting factor VIII
  • HSCT for an adult, adolescent, or pediatric allogeneic stem cell transplant recipient who experiences severe hypogammaglobulinemia (IgG ≤400 mg/dL)
  • HIES (Hyper-IgE syndromes, Job 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)
  • 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 ≤400 mg/dL) is present
  • Solid organ transplant among sensitized transplant candidates, and antibody-mediated rejection (AMR) 
Infectious Disease

  • Toxic shock syndrome​
Neurological and Musculoskeletal Disorders

  • Acute disseminated encephalomyelitis (ADEM)
  • CIDP
  • Dermatomyositis (DM) and polymyositis (PM) 
  • Guillain-Barré 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 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

Cutaquig, Cuvitru, Hizentra, HyQvia, and Xembify are brand names of SCIG products that are currently on the market. There are also certain IVIG products (e.g., Gammagard Liquid, Gammaked, Gamunex-C) that can be administered intravenously or subcutaneously. Although there are several brands of IVIG and SCIG on the market approved for the treatment of PIDD ​​or CIDP, 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.

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 one or more 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
  • HIES (Hyper-IgE syndromes, Job syndrome) when all of the following signs and symptoms are present:
    • ​The individual has eosinophilia (500 or more eosinophils/μL)
    • The individual has elevated serum IgE (>2000 IU/mL), with normal IgG, IgA, and IgM levels
    • The individual has eczema, recurrent staphylococcal lung infections, and/or skin abscesses documented in office or hospital charts
    • The individual has had a documented failure, contraindication* or intolerance to the subcutaneous administration of one or more of the Company's preferred subcutaneous products (i.e., Gammagard Liquid, Gammaked, or Gamunex-C) (See "Company-Designated Preferred Products" section above and "Not Medically Necessary" section below).
  • PIDD† when the individual has a confirmed genetic diagnosis or laboratory evidence of PIDD or the individual meets both of the following criteria:
    • The 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
    • The 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 to 8 weeks after vaccination
        • A protective (normal) response to each pneumococcal serotype is defined as a titer equal to or greater than 1.3 μg/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 twofold 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 twofold 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: 160 ng N/mL = 1 μ​g/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 fourfold 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 individual has had a documented failure, contraindication* or intolerance to the subcutaneous administration of one or more of ​​the Company's preferred subcutaneous products (i.e., Gammagard Liquid, Gammaked, or Gamunex-C) (See "Company-Designated Preferred Products" section above and "Not Medically Necessary" section below.)
    †The list of PIDDs includes but is not limited to: 
      1. Activated Phosphoinositide 3-kinase Delta Syndrome (APDS) ​
      2. Ataxia-telangiectasia
      3. Autosomal recessive agammaglobulinemia
      4. Caspase-8 deficiency
      5. Combined immunodeficiencies​  
      6. Common variable immunodeficiency (including TACI and ICOS mutation)
      7. DiGeorge syndrome
      8. DOCK (dedicator of cytokinesis 8) deficiency
      9. Griscelli syndrome
      10. Hereditary hypogammaglobulinemia   
      11. Hypogammaglobulinemia, persistent (IgG ≤400 mg/dL or less than two standard deviations [SD] from normal)
      12. IgG-subclass deficiency (deficiency of one or more IgG subclasses to levels less than 2 SD 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.)
      13. Immunodeficiency with increased IgM      
      14. Major histocompatibility complex class I or II deficiency        
      15. Nezelof syndrome                                                                 ​
      16. NEMO (mutations in IKK-gamma) deficiency
      17. Nijmegen breakage syndrome
      18. Purine nucleoside phosphorylase [PNP] deficiency
      19. Selective IgA deficiency with IgG subclass deficiency (reduced serum IgA levels [<7mg/dL] and normal IgG and IgM levels)
      20. Severe combined immunodeficiency (SCID)
      21. SCID due to adenosine deaminase deficiency        
      22. 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
      23. Transient hypogammaglobulinemia of infancy
      24. WHIM (warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis) syndrome
      25. Wiskott-Aldrich syndrome
      26. X-linked agammaglobulinemia (Bruton agammaglobulinemia, congenital agammaglobulinemia)
      27. X-linked and autosomal recessive hyper-IgM syndromes
      28. X-linked immunodeficiency
      29. X-linked lymphoproliferative disease
Neurological and Musculoskeletal Disorders
  • CIDP, when all of the following criteria are met:
    • The individual will begin treatment with SCIG after transitioning from IVIG.
    • ​The individual has progressive or relapsing motor or sensory impairment caused by neuropathy in more than one limb for at least 2 months
    • The individual has at least one of the following electrodiagnostic findings of demyelination: 
      • ​Motor distal latency prolongation in two nerves 
      • Reduction of motor conduction velocity in two nerves 
      • Prolongation of F-wave latency in two nerves 
      • Absence of F-waves in at least one nerve 
      • Motor conduction block in at least one nerve 
      • Abnormal temporal dispersion in at least two nerves 
      • Distal compound muscle action potential (CMAP) duration increase in at least one nerve 
    • 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) (See "Company-Designated Preferred Products" section above and "Not Medically Necessary" section below.)    ​
INTRAVENOUS IMMUNE GLOBULIN (IVIG)
Company-Designated Preferred Products  

​The Company has designated the following preferred and nonpreferred products. Although there are many IVIG​ products on the market, there is no reliable evidence of the superiority of any of these products. The preferred products are less costly and at least as likely to produce equivalent therapeutic results as the nonpreferred products.**
​
PREFERRED IVIG PRODUCTS
NONPREFERRED IVIG PRODUCTS**
Bivigam, ​Flebogamma, Gammagard Liquid, Gammagard S/D, Gammaked, Gammaplex, Gamunex C, Octagam, Privigen, Yimmugo​
Alyglo, Asceniv, Panzyga

Nonpreferred Products**

If the individual has not previously received a nonpreferred IVIG product to treat the specified indication, the nonpreferred product is only ​eligible for coverage when the individual has a documented failure, contraindication* or intolerance to at least two of the Company-designated preferred products.
​
Indications

Use of IVIG therapy (e.g., Alyglo, Asceniv, Bivigam, Flebogamma​, Gammagard Liquid, Gammagard S/D, Gammaked, Gammaplex, Gamunex-C, Octagam, Panzyga, Privigen, Yimmugo) 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 (IVIG for the treatment of autoimmune mucocutaneous blistering disease must be used for short-term therapy, not maintenance therapy​):
    • 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.
  • Stevens-Johnson syndrome or toxic epidermal necrolysis
  • Scleromyxedema
Hematologic
  • 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.
  • 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 ITP when all of the following criteria are met:
    • The individual has a disease duration of greater than 6 months.
    • The individual has no concurrent illness or disease to explain the thrombocytopenia.
    • The individual has platelet counts that remain persistently ≤20,000/mm3.
    • The individual has had splenectomy and/or prior treatment with corticosteroids, unless documented failure, contraindication, or intolerance to corticosteroids exists.
  • Evans syndrome when one of the following criteria is met: 
    • The individual requires a rapid platelet count increase​​
    • The individual has severe thrombocytopenia (platelet counts <30,000/mm3)  
    • The individual has had prior treatment with corticosteroids, unless contraindicated.​  ​​
  • 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
  • SCLS or Clarkson disease when associated with monoclonal gammopathy
Immunodeficiency Syndromes, Primary and Secondary
  • Acquired (secondary) hypogammaglobulinemia in oncologic conditions:
    • CAR T cell ​(anti-CD19) therapy (e.g., axicabtagene ciloleucel [Yescarta], brexucabtagene autoleucel [Tecartus], lisocabtagene maraleucel [Breyanzi], tisagenlecleucel [Kymriah®]) ​for one of the following:
      • ​Acquired hypogammaglobulinemia when the individual has an IgG level of less than 400 to 600 mg/dL and serious or recurrent infections (particularly bacterial) until serum IgG levels normalize and infections resolve​
      • Used for management of the following immunotherapy-related toxicities
        • ​​Further intervention for myocarditis if no improvement within 24 to 48 hours of starting high-dose methylprednisolone
        • Adjunct to rituximab for severe (Grade 3) or life-threatening (Grade 4) bullous dermatitis
        • Stevens-Johnson syndrome, or toxic epidermal necrolysis
        • Moderate, severe, or life-threatening (G2-4) steroid-refractory myositis (proximal muscle weakness, neck flexor weakness, with or without myalgias) for significant dysphagia, life-threatening situations, or cases refractory to corticosteroids
        • Severe (G3-4) myasthenia gravis
        • Moderate (G2) or severe (G3-4) Guillain-Barré syndrome or severe (G3-4) peripheral neuropathy in combination with high-dose methylprednisolone
        • Encephalitis in combination with high-dose methylprednisolone if severe or progressing symptoms (strongly consider if progressing over 24 hours)
        • Demyelinating disease (optic neuritis, transverse myelitis, acute demyelinating encephalomyelitis)
        • Moderate (G3) pneumonitis if no improvement after 48 to 72 hours of corticosteroids or severe (G3-4) pneumonitis if no improvement after 48 hours of methylprednisolone​
        • Life-threatening (G4) cytokine release syndrome that is refractory to high-dose corticosteroids and anti-IL-6 therapy
    • 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 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)
  • 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 ≤400 mg/dL)
  • HIES (Hyper-IgE syndromes, Job syndrome) when all of the following signs and symptoms are present:
    • Individual has eosinophilia (500 or more eosinophils/μL).
    • 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 <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 1-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])
    • Myocarditis if no improvement within 24​ to 48 hours of starting pulse-dose methylprednisolone​
    • Adjunct to rituximab for severe (Grade 3) or life-threatening (Grade 4) bullous dermatitis ​​​
    • Stevens-Johnson syndrome, or toxic epidermal necrolysis
    • Moderate or severe (G2-3) steroid-refractory myalgias or myositis (muscle weakness), or life-threatening (G4) steroid-refractory myositis
    • Severe (Grade 3-4) myasthenia gravis
    • 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 (strongly consider if progressing over 24 hours)​
    • Transverse myelitis
    • Moderate (G3) pneumonitis if no improvement after 48 to 72 hours of corticosteroids or severe (G3-4) pneumonitis if no improvement after 48 hours of methylprednisolone​
  • ​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
  • 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 to 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 twofold 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 twofold 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: 160 ng N/mL = 1 μg/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 fourfold 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. APDS ​
      2. Ataxia-telangiectasia
      3. Autosomal recessive agammaglobulinemia
      4. Caspase-8 deficiency
      5. Combined immunodeficiencies​  
      6. Common variable immunodeficiency (including TACI and ICOS mutation)
      7. DiGeorge syndrome
      8. DOCK (dedicator of cytokinesis-8) deficiency
      9. Griscelli syndrome
      10. Hereditary hypogammaglobulinemia   
      11. Hypogammaglobulinemia, persistent (IgG ≤400 mg/dL or less than two SD from normal)
      12. IgG-subclass deficiency (deficiency of one or more IgG subclasses to levels less than 2 SD 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.)
      13. Immunodeficiency with increased immunoglobulin M [IgM]      
      14. Major histocompatibility complex class I or II deficiency           
      15. Nezelof syndrome                                                                  ​
      16. NEMO (mutations in IKK-gamma) deficiency
      17. Nijmegen breakage syndrome
      18. PNP deficiency
      19. Selective IgA deficiency with IgG subclass deficiency (reduced serum IgA levels [<7mg/dL] and normal IgG and IgM levels)
      20. SCID
      21. SCID due to adenosine deaminase deficiency                 
      22. 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
      23. Transient hypogammaglobulinemia of infancy
      24. WHIM syndrome
      25. Wiskott-Aldrich syndrome
      26. X-linked agammaglobulinemia (aka, Bruton's agammaglobulinemia, congenital agammaglobulinemia)
      27. X-linked and autosomal recessive hyper-IgM syndromes
      28. X-linked immunodeficiency
      29. 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 ≤400 mg/dL) is present
  • Solid organ transplant amongst sensitized transplant candidates, ​and 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
  • ADEM
    • Rescue therapy for individuals unresponsive/refractory to, intolerant of, or who have a contraindication to, corticosteroids.
  • ​CIDP, when all of the following criteria are met:
    • ​​​The individual has progressive or relapsing motor or sensory impairment caused by neuropathy in more than one limb for at least 2 months​
    • The individual has at least one of the following electrodiagnostic findings of demyelination: 
      • Motor distal latency prolongation in two nerves 
      • ​Reduction of motor conduction velocity in two nerves 
      • Prolongation of F-wave latency in two nerves 
      • Absence of F-waves in at least one nerve 
      • Motor conduction block in at least one nerve 
      • Abnormal temporal dispersion in at least two nerves 
      • Distal CMAP duration increase in at least one nerve 
  • DM or 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, examination, and electromyography/nerve conduction studies [EMG/NCS]) 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 4-month trial of steroids and/or immunosuppressants.
  • Guillain-Barré 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 examination 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]).
  • 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 examination 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
  • NMO (Devic syndrome)
    • The individual is unresponsive/refractory to, intolerant of, or has a contraindication to ​other standard therapies (e.g., corticosteroids and azathioprine).
  • Rasmussen encephalitis
    • In individuals with intractable focal motor seizure​s and progressive neurologic deterioration (dementia, hemiparesis)
  • Relapsing-remitting 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 examination at the time of initial therapy.
    • The individual is refractory to other standard therapies (e.g., interferons) given in therapeutic doses over at least 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)
  • 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 examination. 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

Coverage of nonpreferred** ​IVIG products are considered not medically necessary and, therefore, not covered because there is no reliable evidence of the superiority of any one brand compared to others and more cost-effective alternatives are available.​

Coverage of nonpreferred ​SCIG products (e.g., Cutaquig, Cuvitru, Hizentra, HyQvia​, and Xembify) are considered not medically necessary and, therefore, not covered for the treatment of PIDD ​or CIDP 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 ​one or more 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​ disease
  • Autism
  • Hemolytic uremic syndrome
  • Multiple sclerosis (MS): 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)
  • Small fiber neuropathy     ​
  • Yellow nail syndrome
NOT ELIGIBLE FOR REIMBURSEMENT

Carimune NF​ is ​no longer manufactured and has been withdrawn from the market; therefore, it is 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 postpayment 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.

STANDARD WRITTEN 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 (WHEN APPLICABLE)

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 30 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 10 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.


The maximum number of supplies that can be dispensed at one time is no more than a 1-month supply.​​

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 primary immunodeficiency disorders (PIDD). Supplemental approvals for Gammagard S/D®​ have since been issued by the FDA.

In 2003, the FDA approved both Gamunex-C and Gammaked 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 idiopathic thrombocytopenic purpura (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. Supplemental approval for HyQvia ​has since been issued by the FDA.

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 percent solution for the treatment of PIDD and chronic ITP.

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

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

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

On December 15, 2023, the FDA approved Alyglo, Immune Globulin Intravenous, human-stwk, 10 percent​ solution for the treatment of PIDD.

​On June 13, 2024, the FDA approved Yimmugo, immune globulin intravenous, human-dira, 10 percent 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 Immunopharmacol. 2016;34:25-31.

Alcantara M, Barnett C, Katzberg H, Bril V. An update on the use of immunoglobulins as treatment for myasthenia gravis. Expert Rev Clin Immunol. 2022 Jul;18(7):703-715. 
Alyglo. immune globulin intravenous, human-stwk. GC Biopharma Corp.Teaneck, NJ. Available at: ALYGLO | FDA. Accessed December 27, 2023. 

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 allograft rejection. UpToDate Website. 12/07/2022. Available at: https://www.uptodate.com/contents/pancreas-allograft-rejection?source=search_result&search=antibody mediated rejection&selectedTitle=10~150. Accessed December 8, 2023. 

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 2024. Immune Globulin. updated 02/08/2021. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed January 11, 2024.​

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.

Arnold DM, Cuker A. Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults​. 10/11/2023. Available at: Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults - UpToDate. Accessed December 28, 2023. 

Arnold DM, Cuker A, Kelton JG. Initial treatment ​of immune thrombocytopenia in adults. UpToDate Website. 01/24/2022. Available at: https://www.uptodate.com/contents/immune-thrombocytopenia-itp-in-adults-initial-treatment-and-prognosis?source=search_result&search=ITP&selectedTitle=2~150. Accessed December 8, 2023. 

Audia S, Grienay N, Mounier M, Michel M, Bonnotte B. Evans' Syndrome: From Diagnosis to Treatment. J Clin Med. 2020 Nov 27;9(12):3851. 

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

Ballow M. Primary immunodeficiency disorders: antibody deficiency. J Allergy Clin Immunol. 2002 Apr;109(4):581-91.

Ballow M, Fleisher TA. Secondary immunodeficiency induced by biologic therapies. UpToDate Website. 09/15/2023. Available at: https://www.uptodate.com/contents/secondary-immunodeficiency-induced-by-biologic-therapies?source=search_result&search=secondary immunodeficiency&selectedTitle=3~74. Accessed December 8, 2023. ​

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.

Barth D, Nabavi Nouri M, Ng E, et al. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 2011; 76:2017.

Bayry J, Hartung HP, Kaveri SV. FORUM IVIg for relapsing-remitting multiple sclerosis: promises and uncertainties. Trends Pharmacol Sci. 2015;36(7):419-421.

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.

Bird SJ. Overview of the treatment of myasthenia gravis. 08/17/2023. UpToDate Website. Available at: https://www.uptodate.com/contents/treatment-of-myasthenia-gravis?source=search_result&search=myasthenia gravis&selectedTitle=4~150. Accessed December 8, 2023.  ​

Bird SJ, Levine JM. Myasthenic crisis. 06/16/2023. UpToDate Website. Available at: https://www.uptodate.com/contents/myasthenic-crisis?source=see_link. Accessed December 8, 2023. ​

Blimark C, Holmberg E, Mellqvist UH, et al. Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. Haematologica. 2015 Jan;100(1):107-13.

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

Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136:1186.

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.

Brugnara C, Brodsky RA. Warm autoimmune hemolytic anemia (AIHA) in adults. UpToDate Website. 06/06/2023. Available at: Warm autoimmune hemolytic anemia (AIHA) in adults - UpToDate​. Accessed December 27, 2023.

Buckley RH. Primary defects of antibody production. In: Kliegman RM, Stanton BF, St Geme JW, Schor NF, eds. Nelson Textbook of Pediatrics. 20th ed. Philadelphia, PA: Elsevier; 2016:chap 124.

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. 11/27/2023. 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 December 8, 2023. ​

Butte MJ. Laboratory evaluation of the immune system. 02/02/2023. Available at: http://www.uptodate.com/contents/laboratory-evaluation-of-the-immune-system?source=search_result&search=laboratory+evidence+of+the+immune+system&selectedTitle=3~150. Accessed December 8, 2023. ​

Calhoun KA, Bahr T. Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management. [UpToDate Website]. 03/08/2023. Available at: https://www.uptodate.com/contents/postnatal-diagnosis-and-management-of-hemolytic-disease-of-the-fetus-and-newborn?source=search_result&search=hemolytic disease of the newborn&selectedTitle=1~150 [via subscription only]. Accessed December 8, 2023. 

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 8, 2023.

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 December 8, 2023.​

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.

Cholera M, Chainani-Wu N. Management of pemphigus vulgaris. Adv Ther. 2016;33:910-958.

Chu VH. Staphylococcal toxic shock syndrome. UpToDate Website. 04/19/2022. Available at: https://www.uptodate.com/contents/staphylococcal-toxic-shock-syndrome?source=search_result&search=toxic shock syndrome&selectedTitle=1~141. Accessed December 8, 2023. ​

Coates TD. Immune neutropenia. UpToDate. 05/01/2023. Available at: https://www.uptodate.com/contents/immune-neutropenia?source=search_result&search=autoimmune neutropenia&selectedTitle=1~50. Accessed December 8, 2023. ​

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.

Cutaquig. Immune Globulin Subcutaneous (Human), 16.5% Solution. Approval and prescribing information. Octapharma USA INC.:Paramus, NJ. 11/2021. Available at: Subcutaneous Immunoglobulin Therapy for Adult PI | cutaquig® (cutaquigusa.com). Accessed September 27, 2023.​

Cuvitru, Immune Globulin Subcutaneous (Human), 20% Solution approval and prescribing information. Baxalta US Inc.: Lexington, MA. 03/2023. Available at: https://www.cuvitru.com/. Accessed January 11, 2024. ​

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.

Elsevier’s Clinical Pharmacology Compendium. Immune Globulin IV, IVIG, IGIV. [Clinical Key Web site]. 12/26/2023. Available at: https://www.clinicalkey.com/pharmacology/monograph/311?sec=monindi [via subscription only]. Accessed January 11, 2024. ​
​
Elsevier’s Clinical Pharmacology Compendium. Immune Globulin SC, SCIG, IGSC. [Clinical Key Web site]. 05/11/2023. Available at: https://www.clinicalkey.com/pharmacology/monograph/3470?sec=monindi#233 [via subscription only]. Accessed January 11, 2024. 

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.

Erkan D, Ortel TL. Management of antiphospholipid syndrome. 11/08/2022. Available at: http://www.uptodate.com/contents/treatment-of-the-antiphospholipid-syndrome?source=search_result&search=&selectedTitle=2~69 [via subscription only]. Accessed December 8, 2023. 

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.

Feldman AG, Whittington PF. Neonatal hemochromatosis. J Clin Exp Hepatol. 2016;3:313-320.

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Watt T, Warshaw B, Katzenstein HM. Atypical hemolytic uremic syndrome responsive to steroids and intravenous immune globulin. Pediatr Blood Cancer. 2009 Jul;53(1):90-91.

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. 04/12/2023. 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 December 11, 2023.​

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.

Truven Health Analytics Inc. Micromedex® Solutions. DrugDex®. [Internet database]. Immune Globulin. 11/14/2023. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ [via subscription only]. Accessed December 11, 2023. 

 Myocarditis (Acute)

Allan CK, Fulton DR. Treatment and prognosis of myocarditis in children. UpToDate Website. 06/28/2023. Available at: https://www.uptodate.com/contents/treatment-and-prognosis-of-myocarditis-in-children?source=search_result&search=myocarditis&selectedTitle=5~150. Accessed December 11, 2023.​

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

Cooper LT. Treatment and prognosis of myocarditis in adults. UpToDate Website. 08/11/2022. Available at: https://www.uptodate.com/contents/treatment-and-prognosis-of-myocarditis-in-adults?source=search_result&search=myocarditis&selectedTitle=2~150. Accessed December 11, 2023.​​

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;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. 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;8(8):CD004370.

Schauer J, Newland D, Hong B, et al. Treating Pediatric Myocarditis with High Dose Steroids and Immunoglobulin. Pediatr Cardiol. 2023;44(2):441-450.
Neonatal sepsis treatment

Cantey JB, Edwards MS. Management and outcome of sepsis in term and late preterm infants. UpToDate Website. 10/18/2023. 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 December 11, 2023.​​

Gollehon NS. Neonatal sepsis treatment and management. Medscape. 06/13/19. Available at: http://emedicine.medscape.com/article/978352-treatment#d8. Accessed December 11, 2023.​

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. 01/10/2022. 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 December 11, 2023.

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 

Abboud H, Probasco JC, Irani S, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021;92(7):757-768. 

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. Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis. UpToDate Website. 11/28/2023. Available at: http://www.uptodate.com/contents/paraneoplastic-and-autoimmune-encephalitis?source=search_result&search=paraneoplastic+limbic+encephalitis&selectedTitle=1~2#H2380193. Accessed December 11, 2023.​​

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

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.
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. 11/2023. Available at: https://rarediseases.info.nih.gov/diseases/8742/limbic-encephalitis. Accessed December 11, 2023.

Sharma A, Dubey D, Sawhney A, Janga K. GAD65 Positive Autoimmune Limbic Encephalitis: A Case Report and Review of Literature. J Clin Med Res. 2012;4(6):424-428. 

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.

Uy CE, Binks S, Irani SR. Autoimmune encephalitis: clinical spectrum and management. Pract Neurol. 2021;21(5):412-423. 
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):872-873. 

American Academy of Allergy, Asthma and Immunology. Position statement on the appropriate use of intravenously administered immunoglobulin (IGIV). January 2005. Available at: https://www.aaaai.org/Aaaai/media/Media-Library-PDFs/Practice Management/Practice Tools/IGIV-2005.pdf.

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;89:149-153.

Frankovich J, Swedo SE, Murphy TK, et al. Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II—Use of Immunomodulatory Therapies. J Child Adolesc Psychopharmacol. 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):118-124. 

Gilbert DL, Kurlan R. PANDAS: horse or zebra? Neurology. 2009;73(16):1252-1253.

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):177-182.

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):65-69.

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.

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):45-48.

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

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 December 11, 2023.

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 streptoc​occi. 04/25/2022. 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 December 11, 2023.​

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 globu​lin 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):127-130.

Sigra S, Hesselmark E, Bejerot S. Treatment of PANDAS and PANS: a systematic review. Neurosci Biobehav Rev. 2018;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):957-959.

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.

Alder Y, Imazio M. Recurrent pericarditis. 06/30/2022. UpToDate Website. Available at: https://www.uptodate.com/contents/recurrent-pericarditis?search=pericarditis&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3. Accessed December 11, 2023.
Baskar S. Pediatric pericarditis. American College of Cardiology Website. 06/08/16. Available at: https://www.acc.org/latest-in-cardiology/articles/2016/06/08/11/43/pediatric-pericarditis.

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. 09/22/2022. 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 December 11, 2023. ​

National Institute of Neurological Disorders and Stroke. Charcot-Marie-Tooth disease. 11/28/2023. Available at: https://www.ninds.nih.gov/health-information/disorders/charcot-marie-tooth-disease?search-term=charcot-marie-tooth-disease. Accessed December 11, 2023. ​​

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 December 11, 2023. 

Postural Tachycardia Syndrome (POTS)

Cheshire WP. Postural tachycardia syndrome. Up-To-Date Website. Updated 02/14/2023. Available at: http://www.uptodate.com/contents/postural-tachycardia-syndrome. Accessed December 11, 2023. ​​

 Grubb BP. Postural tachycardia syndrome. Circulation. 2008;117(21) 2814-2817.

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 11/28/2023. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Postural-Tachycardia-Syndrome-Information-Page. Accessed December 11, 2023. 

Small fiber neuropathy 
​
Geerts M, de Greef BTA, Sopacua M, et al. Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy. Neurology. 2021;18;96(20):e2534-e2545. 

Gibbons CH, Rajan S, Senechal K, et al. A double-blind placebo-controlled pilot study of immunoglobulin for small fiber neuropathy associated with TS-HDS and FGFR-3 autoantibodies. Muscle Nerve. 2023;67(5):363-370. 

Hanewinckel R, Ikram MA, Van Doorn PA. Peripheral neuropathies. Handb Clin Neurol. 2016;138:263-82.

Liu X, Treister R, Lang M, Oaklander AL. IVIg for apparently autoimmune small-fiber polyneuropathy: first analysis of efficacy and safety. Ther Adv Neurol Disord. 2018;8;11:1756285617744484. 

Parambil JG, Tavee JO, Zhou L, Pearson KS, Culver DA. Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med. 2011;105(1):101-105.  

Strand N, Wie C, Peck J, et al. Small Fiber Neuropathy. Curr Pain Headache Rep. 2022;26(6):429-438. 

Tavee JO, Karwa K, Ahmed Z, et al. Sarcoidosis-associated small fiber neuropathy in a large cohort: Clinical aspects and response to IVIG and anti-TNF alpha treatment. Respir Med. 2017;126:135-138. 

Zeidman LA, Saini P, Mai P. Immune-mediated small fiber neuropathy with trisulfated heparin disaccharide, fibroblast growth factor receptor 3, or plexin D1 antibodies: presentation and treatment with intravenous immunoglobulin. J Clin Neuromuscul Dis. 2022;24(1):26-37.

Yellow Nail Syndrome

 Cheslock M, Harrington DW. Yellow Nail Syndrome. 2022 Sep 19. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. 

Gupta S, Samra D, Yel L, Agrawal S. T and B cell deficiency associated with yellow nail syndrome. Scand J Immunol. 2012;75(3) 329-335.

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) 375-381.

Maldonado F, Ryu JH. Yellow nail syndrome. Curr Opin Pulm Med. 2009;15(4):371-375.

National Association for Rare Disorders. Yellow nail syndrome. 2022. Available at: https://rarediseases.org/rare-diseases/yellow-nail-syndrome/. Accessed December 11, 2023. 

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.​

Other Indications


Şahlı E, Gündüz K. Thyroid-associated Ophthalmopathy. Turk J Ophthalmol. 2017;47(2):94-105.​​

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)

J1555 Injection, immune globulin (cuvitru), 100 mg

J1558 Injection, immune globulin (xembify), 100 mg

J1559 Injection, immune globulin (Hizentra), 100 mg

J1561 Injection, immune globulin, (Gamunex/Gamunex-C/Gammaked), nonlyophilized (e.g., liquid), 500 mg

J1569 Injection, immune globulin, (gammagard liquid/gammagard liquid erc), non-lyophilized, (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:

J1551 Injection, immune globulin (cutaquig), 100 mg


INTRAVENOUS IMMUNE GLOBULIN (IVIG)

J1459 Injection, immune globulin (Privigen), intravenous, non-lyophilized (e.g. liquid), 500 mg

J1552 Injection, immune globulin (alyglo), 500 mg

J1553 Injection, immune globulin (yimmugo), 100 mg

J1554 Injection, immune globulin (asceniv), 500 mg

J1556 Injection, immune globulin (bivigam), 500 mg

J1557 Injection, 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

J1569 Injection, immune globulin, (gammagard liquid/gammagard liquid erc), non-lyophilized, (e.g., liquid), 500 mg

J1572 Injection, immune globulin, (Flebogamma/Flebogamma Dif), intravenous, nonlyophilized (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 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 08.00.13ao:
​​10/28/2026
​This policy has been reissued in accordance with the Company's annual review process. ​
07/01/2026

This version of the policy will become effective 07/01/2026.

The following HCPCS narrative has been revised in this policy:

FROM: J1569 Injection, immune globulin, (gammagard liquid), non-lyophilized, (e.g., liquid), 500 mg

TO: J1569 Injection, immune globulin, (gammagard liquid/gammagard liquid erc), non-lyophilized, (e.g., liquid), 500 mg


Revisions From 08.00.13an:
04/01/2026

This version of the policy will become effective 04/01/2026​.

The following HCPCS code has been removed from this policy:
J1599 Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500 mg

The following HCPCS code has been added to this policy:
J1553 Injection, immune globulin (yimmugo), 100 mg

Revisions From 08.00.13am:
01/01/2026​

This version of the policy will become effective 01/01/2026.

This policy has been updated to communicate the Company's preferred intravenous immune globulin (IVIG) product designation. All IVIG products are preferred, with the exception of the following nonpreferred products: Asceniv, Panzga, Alyglo​.

The new IVIG product, Yimmugo, has been added to this policy, represented by HCPCS code J1599 Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500 mg.

The following HCPCS codes have been removed from this policy:
J1562 Injection, immune globulin (vivaglobin), 100 mg
J1572 Injection, immune globulin, (flebogamma/flebogamma dif), intravenous, non-lyophilized (e.g., liquid), 500 mg​
-----------------------------------------------------------------------------------------------------------------

On 01/13/2026, the policy was revised in reaction to CMS guidance to NOT delete HCPCS J1572.    

 

This policy has been identified for the HCPCS code update, effective 01/01/2026.

 

The following HCPCS code has been added:

J1572 Injection, immune globulin, (flebogamma/flebogamma dif), intravenous, non-lyophilized (e.g., liquid), 500 mg


Revisions From 08.00.13al:
10/01/2025

This version of the policy will become effective 10/01/2025.


The following ICD-10 CM codes have been removed from this policy:

D71 Functional disorders of polymorphonuclear neutrophils
G35 Multiple sclerosis

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

G35.A Relapsing-remitting multiple sclerosis


Revisions From 08.00.13ak:
01/01/2025

This version of the policy will become effective 01/01/2025.


The following Healthcare Common Procedure Coding System (HCPCS) code has been added to this policy:
  • ​J1552 Injection, immune globulin (alyglo), 500 mg​

The following HCPCS code has been removed from this policy, which was used to represent immune globulin intravenous, human-stwk (Alyglo):
  • J1599   Injection, immune globulin, intravenous, nonlyophilized​ (e.g., liquid), not otherwise specified, 500 mg​​​
​
Revisions From ​08.00.13aj:
10/14/2024

​​This version of the policy will become effective 10/14/2024.​


This policy has been updated to communicate the Medically Necessary coverage position of Intravenous Immune Globulin (IVIG) and Subcutaneous Immune Globulin (SCIG)​​ for the following:
  • Primary Immunodefi​ciency Disorder (PIDD)​ examples​
    • Activated Phosphoinositide 3-kinase Delta Syndrome (APDS) 
    • Combined immunodeficiencies​​
    • Hereditary hypogammaglobulinemia
    • Immunodeficiency with increased immunoglobulin M [IgM]  
    • Major histocompatibility complex class I or II deficiency     
    • Nezelof syndrome​
    • Severe combined immunodeficiency due to adenosine deaminase deficiency  
  • Chronic inflammatory demyelinating polyneuropathies (CIDP) with revised criteria, per diagnostic testing
This policy has been updated to communicate the Medically Necessary coverage position of IVIG for the following:
  • New product, Alyglo (immune globulin intravenous, human-stwk) 10% immune globulin
  • Evans syndrome, when the criteria, including Dosing and Frequency, are met
  • Toxicity management, related to chimeric antigen receptor (CAR) T cell​ or immune checkpoint inhibitors revised criteria 
  • Dosing and Frequency revisions in Attachment A were made to the following:
    • Chronic refractory idiopathic thrombocytopenic purpura (ITP)
    • Acquired (secondary) hypogammaglobulinemia in oncologic conditions
    • Immune checkpoint inhibitor-related toxicities, management
    • Kawasaki disease
    • PIDD associated with defects in immunity
    • Acute and chronic antibody-mediated rejection (AMR) 
    • Chronic inflammatory demyelinating polyneuropathies (CIDP)
    • Myasthenia gravis syndrome 
    • Relapsing-remitting multiple sclerosis​
This policy has been updated to communicate the Medically Necessary coverage position of SCIG for the following:
  • ​Clarification for one preferred product (not all three) necessity to be considered prior to coverage of a non-preferred product
  • CIDP: HyQvia
  • Dosing and Frequency revisions in Attachment A were made to the following:​
    • PIDD: Cutaquig, Hizentra
    • CIDP: Hizentra​
Small fiber neuropathy indication was added to the Experimental/Investigational Section for IVIG. 
Autoimmune encephalopathy indication was removed from the Experimental/Investigational Section for IVIG. ​

The following International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code has been added to this policy for SCIG and IVIG:
D81.31 Severe combined immunodeficiency due to adenosine deaminase deficiency​

The following ICD-10-CM codes have been added to this policy for IVIG:
  • D69.41 Evans syndrome​
  • D89.834 Cytokine release syndrome, grade 4
  • ​J98.4 Other disorders of lung​

The following ICD-10-CM codes have been removed from the coding table, due to unspecified laterality:

  • M60.819 Other myositis, unspecified shoulder
  • M60.829 Other myositis, unspecified upper arm
  • M60.839 Other myositis, unspecified forearm
  • M60.849 Other myositis, unspecified hand
  • M60.859 Other myositis, unspecified thigh
  • M60.869 Other myositis, unspecified lower leg
  • M60.879 Other myositis, unspecified ankle and foot
​
The following Healthcare Common Procedure Coding System (HCPCS) code has been added to this policy and is used to represent immune globulin intravenous, human-stwk (Alyglo):
  • J1599   Injection, immune globulin, intravenous, nonlyophilized​ (e.g., liquid), not otherwise specified, 500 mg​​​

Revisions From 08.00.13ai:
10/01/2024

This version of the policy will become effective 10/01/2024.

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

C88.90 Malignant immunoproliferative disease, unspecified not having achieved remission
C88.91 Malignant immunoproliferative disease, unspecified, in remission
G40.843 KCNQ2-related epilepsy, intractable, with status epilepticus
G40.844 KCNQ2-related epilepsy, intractable, without status epilepticus​

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 bacterial 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 number:
  • 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.​
7/1/2026
7/1/2026
10/28/2026
08.00.13
Medical Policy Bulletin
Commercial
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Independence Blue Cross is a subsidiary of Independence Health Group, Inc. — independent licensees of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.