Description  
Immunoglobulins are derived from human donor plasma and used to treat an array of disorders, including primary and secondary immune deficiency states and various autoimmune and inflammatory disorders. Human immunoglobulin therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G antibodies against a wide variety of bacterial and viral antigens. This evidence review addresses the use of human immunoglobulin therapy for preventing and/or treating disorders in the outpatient setting. Both intravenous immunoglobulin (IVIG) infusion and subcutaneous immunoglobulin (SCIG) infusion are addressed. However, the review only considers nonspecific pooled preparations of IVIG; it does not consider other preparations used for passive immunization to specific antigens.

Immunodeficiency States
For individuals who have primary humoral immunodeficiency who receive IVIG or SCIG therapy, the evidence includes multiple randomized controlled trials (RCTs) and noncomparative studies. The relevant outcomes are overall survival (OS), symptoms, change in disease status, morbid events, functional outcomes, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG and SCIG therapy improved disease-related outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are undergoing hematopoietic cell transplantation who receive IVIG therapy (prophylaxis), the evidence includes multiple RCTs, systematic reviews, and a meta-analysis. The relevant outcomes are disease-specific survival (DSS), symptoms, change in disease status, morbid events, quality of life (QOL), hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG for routine prophylaxis of infection in patients undergoing hematopoietic cell transplantation was not associated with survival benefit or reduction in infection. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who are at risk of acute antibody-mediated rejection after solid organ transplants who receive IVIG therapy, the evidence includes multiple RCTs, noncomparative observational studies, systematic reviews, and meta-analysis. The relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG for prophylaxis of infection in patients with high panel reactive antibody levels was not associated with a survival benefit or reduction in infection. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have acute antibody-mediated rejection after solid organ transplants who receive IVIG therapy, the evidence includes retrospective case series and a systematic review. The relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG treatment for antibody-mediated rejection has shown potential benefits in retrospective or small prospective studies. Larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Infections
For individuals who have chronic lymphocytic leukemia with recurrent bacterial infections associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for recurrent bacterial infections associated with hypogammaglobulinemia in chronic lymphocytic leukemia patients has shown reductions in minor and moderate infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are HIV-infected children with recurrent bacterial infection associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes a single RCT. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for the prevention of opportunistic infections in HIV-infected children has shown reductions in minor and serious infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are preterm and low birth weight infants and at risk for sepsis who receive IVIG therapy (prophylaxis), the evidence includes multiple RCTs and a systematic review. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for prophylaxis of neonatal sepsis has shown a 3% reduction in sepsis and a 4% reduction in 1 or more episodes of any serious infection without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who are preterm and low birth weight infants with sepsis who receive IVIG therapy (treatment), the evidence includes multiple RCTs and a systematic review. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for neonatal sepsis did not differ significantly in the rates of death or major disability. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who are adults with sepsis who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for adult sepsis showed reductions in mortality in the meta-analysis. However, multiple factors preclude recommending the routine use of IVIG to treat sepsis. They include the preponderance of small low-quality studies, the use of heterogeneous dosing regimens, types of IVIG preparations used, and changes over time in the management of sepsis. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have severe anemia associated with human parvovirus B19 who receive IVIG therapy, the evidence includes case series. The relevant outcomes are a change in disease status, treatment-related mortality, and treatment-related morbidity. Although observed improvements in outcomes have suggested potential benefits with IVIG therapy, data are retrospective. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have toxic shock syndrome who receive IVIG therapy, the evidence includes a small RCT and multiple observational studies. The relevant outcomes are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for toxic shock syndrome in adult women has shown reductions in mortality in the small RCT and in multiple observational studies. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Autoimmune and Inflammatory Conditions
For individuals who have idiopathic thrombocytopenic purpura who receive IVIG therapy, the evidence includes multiple RCTs, a systematic review, a meta-analysis, and noncomparative studies. The relevant outcomes are DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with corticosteroids, IVIG therapy improved platelet counts. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have Guillain-Barré syndrome who receive IVIG therapy, the evidence includes multiple RCTs, a systematic review, and a meta-analysis. The relevant outcomes are OS, DSS, symptoms, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with plasma exchange or combination therapy with plasma exchange, IVIG therapy showed similar outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have Kawasaki disease who receive IVIG therapy, the evidence includes multiple RCTs, a systematic review, and a meta-analysis. The relevant outcomes are disease-specific mortality, change in disease status, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown significant decreases in new coronary artery abnormalities. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have granulomatosis with polyangiitis (Wegener granulomatosis) who receive IVIG therapy, the evidence includes systematic reviews and an RCT. The relevant outcomes are disease-specific mortality, change in disease status, and treatment-related mortality and morbidity. The success of IVIG in Kawasaki disease has led to the investigation of IVIG therapy for other vasculitides such as Wegener granulomatosis. A 2013 Cochrane review identified 1 RCT on IVIG for Wegener granulomatosis. This small trial found significantly more responders in the IVIG treatment group at three months-but no significant differences after three months, or in the frequency of relapse or use of other medications. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have chronic inflammatory demyelinating polyneuropathy (CIDP) who receive IVIG therapy, the evidence includes multiple RCTs, a systematic review, and a meta-analysis. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have CIDP who receive SCIG therapy, the evidence includes two RCTs. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Only 1 RCT has directly compared SCIG with IVIG in patients who had CIDP and conclusions about the relative efficacy of the treatments cannot be drawn due to methodologic limitations (e.g., 45% of patients withdrew from the trial). The other RCT demonstrated that the use of SCIG for the maintenance of CIDP might be effective, with relatively low adverse events, but this trial also had a number of limitations (e.g., small sample, 30% dropout rate). The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have multifocal motor neuropathy who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. The relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have Eaton-Lambert myasthenic syndrome who receive IVIG therapy, the evidence includes an RCT and multiple observational studies. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful improvements in outcomes assessing muscle strength and activity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have neuromyelitis optica who receive IVIG therapy, the evidence includes multiple observational studies. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Studies have shown that IVIG treatment may benefit patients who are refractory to first-line treatment with steroids or plasma exchange, particularly children. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have severe refractory myasthenia gravis or myasthenic exacerbation who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. The relevant outcomes are OS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. Compared with plasma exchange, IVIG therapy did not show significantly improved outcomes but was better tolerated. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have relapsing-remitting multiple sclerosis who receive IVIG therapy, the evidence includes multiple RCTs and technology assessments. The relevant outcomes are OS, DSS, symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. According to technology assessments, IVIG therapy is no longer considered a treatment of choice for relapsing-remitting multiple sclerosis. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have autoimmune mucocutaneous blistering diseases who receive IVIG therapy, the evidence includes two RCTs, a systematic review, and multiple uncontrolled studies. The relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. A systematic review found improvements in over 90% of patients. RCTs have reported benefits in disease activity in the population as a whole (one trial) or subgroup of patients with severe disease (one trial). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have toxic epidermal necrosis or Stevens-Johnson syndrome who receive IVIG therapy, the evidence includes systematic reviews of observational studies. The relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. No RCTs have evaluated IVIG for toxic epidermal necrosis or Stevens-Johnson syndrome; most trials that have, have been uncontrolled. A 2016 pooled analysis of data from 11 studies did not find a statistically significant benefit of IVIG therapy for mortality. Compared with placebo, IVIG therapy has not shown statistically significant benefits for mortality. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have dermatomyositis or polymyositis who receive IVIG therapy, the evidence includes two RCTs, multiple noncomparative observational studies, and a systematic review. The relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. In one of the RCTs, compared with placebo, IVIG therapy showed improvements in muscle strength. A large case series also noted improvements in most patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have inclusion body myositis who receive IVIG therapy, the evidence includes multiple RCTs. The relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy failed to show improvements in muscle strength. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have systemic lupus erythematosus who receive IVIG therapy, the evidence includes an RCT, multiple observational studies, and a meta-analysis. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Although observed improvements in outcomes have suggested potential benefit with IVIG therapy for surrogate outcomes, data are retrospective. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have immune optic neuritis who receive IVIG therapy, the evidence includes two RCTs. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show improvements in vision-related outcomes. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have Crohn disease who receive IVIG therapy, the evidence includes multiple case reports of single patients summarized in a systematic review. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, treatment-related mortality and treatment-related morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have hemophagocytic lymphohistiocytosis who receive IVIG therapy, the evidence includes multiple case reports summarized in a systematic review. The relevant outcomes are OS, DSS, change in disease status, QOL, and treatment-related mortality and morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have warm antibody autoimmune hemolytic anemia, refractory to prednisone and splenectomy, who receive IVIG therapy, the evidence includes pooled observational data. The relevant outcomes are a change in disease status, QOL, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested potential benefits with IVIG therapy in select patients. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have antiphospholipid syndrome who receive IVIG therapy, the evidence includes pooled data from a registry. The relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested potential mortality benefit with IVIG therapy. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Alloimmune Processes
For individuals who have neonatal alloimmune thrombocytopenia who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. The relevant outcomes are DSS, change in disease status, and treatment-related mortality and morbidity. Compared with combination use with corticosteroids, IVIG alone did not show any additional increases in platelet counts. Multiple trials have demonstrated increased platelet counts with IVIG therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have a recurrent spontaneous abortion who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. The relevant outcomes are DSS, treatment-related mortality, and treatment-related morbidity. In multiple RCTs, compared with placebo, IVIG therapy alone did not show any beneficial effects in preventing spontaneous abortions. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

Miscellaneous Indications
For individuals who have pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections who receive IVIG therapy, the evidence includes two small RCTs. The relevant outcomes are symptoms, change in disease status, and treatment-related mortality and morbidity. The trials had mixed findings and both had small sample sizes and short intervention duration. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have autism spectrum disorder who receive IVIG therapy, the evidence includes case series. The relevant outcomes are symptoms, change in disease status, functional outcomes, health status measures, QOL, treatment-related mortality and treatment-related morbidity. Although improvements were observed in one case series, the other two reported negative findings. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have complex regional pain syndrome who receive IVIG therapy, the evidence includes an RCT. The relevant outcomes are symptoms, morbid events, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown improvements in pain scores. However, methodologic limitations restrict the conclusions drawn from data on 12 patients. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have Alzheimer disease who receive IVIG therapy, the evidence includes three RCTs. The relevant outcomes are OS, DSS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. With the exception of a few subgroup analyses using mild cognitive impairment status, IVIG therapy was not significantly better than a placebo for outcomes such as brain atrophy, level of plasma amyloid β 1-40, or cognition and function. Studies differed by treatment protocols, outcomes assessed, and two of the three had relatively small sample sizes. Additional RCTs could be conducted to confirm whether IVIG benefits patients with early mild cognitive impairment. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have paraproteinemic neuropathy who receive IVIG therapy, the evidence includes two small RCTs. The relevant outcomes are a change in disease status, QOL and treatment-related mortality and morbidity. Compared with placebo, IVIG showed mild and transitory improvements in one trial but failed to show any improvement in another. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have chronic fatigue syndrome who receive IVIG therapy, the evidence includes an RCT and anecdotal reports. The relevant outcomes are symptoms, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown no therapeutic benefits. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have acute myocarditis who receive IVIG therapy, the evidence includes an RCT, a quasi-randomized trial, and multiple case reports. The relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy failed to show improvements in event-free survival in the RCT while it showed favorable effects on rates of event-free survival in a quasi-randomized study. However, both studies were rated as very low quality and at a high-risk of bias. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have refractory recurrent pericarditis who receive IVIG therapy, the evidence includes multiple case reports and case series. The relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Although improvements were observed in some patients, controlled trials are lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have stiff-person syndrome who receive IVIG therapy, the evidence includes an RCT and multiple case reports. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown decreases in stiffness scores and improvements in functional outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have noninfectious uveitis who receive IVIG therapy, the evidence includes two small case series. The relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. The case series (total n = 28 patients) reported measurable improvements in visual acuity after IVIG therapy, but controlled studies are needed to draw conclusions about the efficacy of IVIG for this population. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have postpolio syndrome who receive IVIG therapy, the evidence includes multiple RCTs, prospective studies, and a meta-analysis. The relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show reductions in the severity of pain and fatigue or improvements in muscle strength. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have necrotizing fasciitis who receive IVIG therapy, the evidence includes an RCT. The relevant outcomes are OS, symptoms, functional outcomes, and treatment-related mortality and morbidity. The RCT found that, compared with placebo, IVIG therapy did not significantly improve functional outcomes, mortality rates, or other outcomes (e.g., the use of life support in the intensive care unit). Additional controlled studies are needed to draw conclusions about the efficacy of IVIG for treating necrotizing fasciitis. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background  
Immunoglobulins are derived from human donor plasma and used to treat an array of disorders, including primary and secondary immunodeficiency states and a variety of autoimmune and inflammatory disorders. Human immunoglobulin therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral antigens. Two formulations of human IgG are available: intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin. Intramuscular immunoglobulin depot injections have been largely abandoned.

IVIG is an antibody-containing solution obtained from the pooled plasma of healthy blood donors that contains antibodies to greater than 10 million antigens. IVIG has been used to correct immunodeficiencies in patients with either inherited or acquired immunodeficiencies and has also been investigated as an immunomodulator in diseases thought to have an autoimmune basis. Several IVIG products are available for clinical use in the United States. A variety of off-label indications have been investigated; some of the most common are inflammatory myopathies, neuropathies (e.g., Guillain-Barré syndrome), myasthenia gravis, multiple sclerosis, and solid organ transplantation.

This evidence review only addresses nonspecific pooled preparations of IVIG; it does not address other immunoglobulin preparations specifically used for passive immunization to prevent or attenuate infection with specific viral diseases (e.g., respiratory syncytial virus, cytomegalovirus, hepatitis B).

IVIG is considered a mainstay of treatment for immunodeficiency conditions and bullous skin disorders. It has been prescribed off-label to treat a wide variety of autoimmune and inflammatory neurologic conditions. 

Regulatory Status 
Several intravenous immunoglobulin (IVIG) products have been approved by the U.S. Food and Drug Administration (FDA). They include Bivigam^® (Biotest) Carimune^® (CSL Behring AG), Flebogamma DIF^® (Instituto Grifols), GammaSTAN S/D^® (Grifols Therapeutics), Gammagard Liquid^® (Baxter), Gammagard S/D^® (Baxter), Gammaplex^® (Bio Products Lab), Gamunex-C^® (Grifols Therapeutics), Octagam^® (Octapharma), and Privigen^® (CSL Behring).¹

Several subcutaneous immunoglobulin products have been approved by FDA. They include Gammagard Liquid^® (Baxter), Gamunex-C^® (Grifols Therapeutics), Cuvitru^® (Baxalta), Hizentra^® CSL (Behring AG), Hyqvia^® (Baxter), and Vivaglobin® CSL (Behring GmbH).¹

At least 1 IVIG product is FDA-approved to treat the following conditions:¹

• Primary humoral immunodeficiency
• Multifocal motor neuropathy
• B-cell chronic lymphocytic leukemia
• Immune (aka idiopathic) thrombocytopenic purpura
• Kawasaki syndrome
• Chronic inflammatory demyelinating polyneuropathy.

Related Policies
80125 Hematopoietic Stem-Cell Transplantation for Autoimmune Diseases
80136 Extracorporeal Photopheresis
80202 Plasma Exchange

Policy
INTRAVENOUS IMMUNOGLOBULIN THERAPY 
Intravenous immunoglobulin (IVIG) therapy may be considered MEDICALLY NECESSARY for the following indications.

Immunodeficiency States
Patients with primary immunodeficiencies, including congenital agammaglobulinemia, hypogammaglobulinemia, common variable immunodeficiency, severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, X-linked hyperimmunoglobulinemia M syndrome, and ataxia telangiectasia.

• Patients with primary immunodeficiency syndromes should meet all the following criteria for treatment with immunoglobulin:
  • Laboratory evidence of immunoglobulin deficiency (see Policy Guidelines section)
  • Documented inability to mount an adequate immunologic response to inciting antigens (see Policy Guidelines section)
  • Persistent and severe infections, despite treatment with prophylactic antibiotics
• Patients undergoing/undergone hematopoietic cell transplantation who have immunoglobulin G (IgG) levels less than 400 mg/dL.
• Prior to solid organ transplant, treatment for patients at high risk of antibody-mediated rejection including highly sensitized patients and those receiving ABO-incompatible organ.

Infections

• Patients with chronic lymphocytic leukemia who have IgG levels less than 400 mg/dL and persistent bacterial infections
• Patients (children) with HIV who have IgG levels less than 400 mg/dL to prevent opportunistic infections
• Patients with severe anemia associated with human parvovirus B19
• Patients with toxic shock syndrome.

Autoimmune and Inflammatory Conditions

• Patients with severe, progressive autoimmune mucocutaneous blistering diseases that include pemphigus, pemphigoid, pemphigus vulgaris, pemphigus foliaceus who have failed treatment with conventional agents such as corticosteroids, azathioprine, and cyclophosphamide
• Patients with acute, severe idiopathic thrombocytopenic purpura (see Policy Guidelines section) or chronic idiopathic thrombocytopenic purpura with at least 6 months of disease duration, presence of symptoms, and with persistent thrombocytopenia (platelet < 20,000 per microliter [adult] or 30,000 per microliter [child]) despite treatment with corticosteroids and splenectomy
• Adult patients with Guillain-Barré syndrome as an equivalent alternative to plasma exchange
• Patients with Kawasaki syndrome
• Patients with Wegener granulomatosis
• Patients with chronic inflammatory demyelinating polyneuropathy with progressive symptoms for at least 2 months with impaired daily activities
• Patients with multifocal motor neuropathy, inability to perform daily activities
• Patients with Eaton-Lambert myasthenic syndrome who have failed to respond to anticholinesterase medications and/or corticosteroids
• Patients with neuromyelitis optica as an alternative for patients with contraindication or lack of response to first-line treatment particularly in children
• Patients with severe refractory myasthenia gravis with chronic debilitating disease despite treatment with cholinesterase inhibitors or complications from or failure of corticosteroids and/or azathioprine
• Patients with myasthenic exacerbation (i.e., an acute episode of respiratory muscle weakness) in whom plasma exchange is contraindicated.
  • One of the following criteria applies to the patient:
    • The patient is experiencing a myasthenic crisis.
    • Other immunosuppressive treatments are ineffective or inappropriate.
    • The patient has weakness that requires hospital admission.
    • The medication will be used prior to surgery or thymectomy.
• Patients with neuromyelitis optica as an alternative for patients with contraindication or lack of response to first-line treatment particularly in children.
• Patients with dermatomyositis or polymyositis that is refractory to treatment with corticosteroids; in combination with other immunosuppressive agents.
• Patients with warm antibody hemolytic anemia who are refractory to prednisone and splenectomy.
  • The patient has symptomatic or severe anemia (Hgb less than 6 g/dL) or thrombocytopenia (platelets less than 20 x10^9/L)
• Patients with antiphospholipid syndrome.
• Patients with dermatomyositis or polymyositis that is refractory to treatment with corticosteroids; in combination with other immunosuppressive agents.

Alloimmune Processes

• Patients with neonatal alloimmune thrombocytopenia
  • Diagnosis of alloimmune thrombocytopenia (fetal-maternal or neonatal)
  • Patient has at least one of the following clinical features:
    • Thrombocytopenia or spontaneous hemorrhage in the fetus
    • Thrombocytopenia in the neonate
    • Unexplained fetal death in a previous pregnancy with the presence of maternal platelet-specific allo-antibodies
• Patients with hemolytic disease of the fetus and newborn (aka erythroblastosis fetalis) 
  • IVIG will be used in combination with phototherapy.

Miscellaneous 

• Patients with stiff person syndrome not controlled by other therapies
  • Patient has autoantibodies to antigens GAD-65 or GAD-67

IVIG therapy is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for the following indications.  

Immunodeficiency States 

• Patients who have received solid organ transplant for prophylaxis or treatment of acute antibody-mediated rejection  

Infections

• Patients with neonatal sepsis (prophylaxis or treatment)
• Patients (adults) with sepsis 

Autoimmune and Inflammatory Conditions 

• Patients with Stevens-Johnson syndrome and toxic epidermal necrolysis
• Patients with inclusion body myositis
• Patients with systemic lupus erythematosus
• Patients with immune optic neuritis
• Patients with Crohn disease
• Patients with hemophagocytic lymphohistiocytosis

Alloimmune Processes

• Patients with recurrent spontaneous abortion  

Miscellaneous 

• Patients with pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections
• Patients with autism spectrum disorder
• Patients with complex regional pain syndrome
• Patients with Alzheimer disease
• Patients with paraproteinemic neuropathy
• Patients with chronic fatigue syndrome
• Patients with acute myocarditis
• Patients with refractory recurrent pericarditis
• Patients with noninfectious uveitis
• Patients with postpolio syndrome
• Patients with thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, paraneoplastic syndromes, epilepsy, chronic sinusitis, asthma, aplastic anemia, Diamond-Blackfan anemia, red cell aplasia, acquired factor VIII inhibitors, acute lymphoblastic leukemia, multiple myeloma, immune-mediated neutropenia, nonimmune thrombocytopenia, cystic fibrosis, recurrent otitis media, diabetes mellitus, Behçet syndrome, adrenoleukodystrophy, organ transplant rejection, Fisher syndrome, IGG subclass deficiency, opsoclonus-myoclonus, birdshot retinopathy, epidermolysis bullosa acquisita, necrotizing fasciitis, polyradiculoneuropathy (other than chronic inflammatory demyelinating polyneuropathy), refractory rheumatoid arthritis, other vasculitides besides Kawasaki disease, including polyarteritis nodosa, Goodpasture syndrome, and vasculitis associated with other connective tissue diseases

GamaSTAN (human immune globulin) may be considered medically necessary for hepatitis A virus prophylaxis or for the prevention or modification of measles in susceptible individuals when the following criteria are met: 

• Exposure has been within no more than the past five (5) days
• The individual is either immunocompromised, younger than 1 year of age, older than 40 years of age, or have cancer, chronic liver and kidney disease

IVIG is considered NOT MEDICALLY NECESSARY for:

• Patients with relapsing-remitting multiple sclerosis

SUBCUTANEOUS IMMUNOGLOBULIN THERAPY
Subcutaneous immunoglobulin therapy may be considered MEDICALLY NECESSARY for the following indications.

• Patients with primary immunodeficiencies, including congenital agammaglobulinemia, hypogammaglobulinemia, common variable immunodeficiency, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and X-linked agammaglobulinemia. 

Other applications of subcutaneous immunoglobulin therapy are considered INVESTIGATIONAL, including but not limited to chronic inflammatory demyelinating polyneuropathy.   

Policy Guidelines
BLACK BOX WARNINGS AND PRECAUTIONS
For the intravenous immunoglobulin (IVIG):

• Thrombosis may occur with immunoglobulin products. Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.
• For individuals at risk of thrombosis, administer immunoglobulin product at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in individuals at risk for hyperviscosity.
• Renal dysfunction, acute renal failure, osmotic nephropathy and death may occur with the administration of human intravenous immunoglobulin intravenous (IVIG) products in predisposed individuals. Individuals predisposed to renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia or individuals receiving known nephrotoxic drugs.
• Renal dysfunction and acute renal failure occur more commonly in individuals receiving IVIG products that contain sucrose.
• For individuals at risk of renal dysfunction or renal failure, administer IVIG at the minimum infusion rate practicable.

Additional warnings and precautions include:

• IgA-deficient individuals with antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions.
• Monitor renal function, including blood urea nitrogen, serum creatinine and urine output, in individuals at risk of developing acute renal failure.
• Hyperproteinemia, increased serum viscosity and hyponatremia may occur in individuals receiving IVIG therapy.
• Thrombosis may occur. Monitor individuals with known risk factors for thrombosis and consider baseline assessment of blood viscosity for those at risk of hyperviscosity.
• Aseptic meningitis syndrome may occur in individuals receiving IVIG therapy, especially with high doses or rapid infusion.
• Hemolytic anemia can develop subsequent to IVIG treatment. Monitor individuals for signs and symptoms of hemolysis and hemolytic anemia.
• Monitor individuals for pulmonary adverse reactions (transfusion-related acute lung injury).
• Individuals receiving IVIG for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks may be at a higher risk for development of fever, chills, nausea and vomiting.
• IVIG is made from human plasma and may contain infectious agents (e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease agent).
• Passive transfer of antibodies may confound serologic testing.

The subcutaneous immunoglobulin product information labels note reactions similar to other immunoglobulin products may occur. The most common adverse reactions with subcutaneous injections include local reactions (i.e., swelling, redness, heat, pain and itching at the injection site).

PRIMARY IMMUNODEFICIENCY SYNDROMES
The diagnosis of immunodeficiency and postimmunization titers must be taken in context with the clinical presentation of the patient and may vary depending on the type of vaccine given and the prior immunization history. The following parameters are examples of criteria for diagnosis of the primary immunodeficiency syndromes. 

• Laboratory evidence of immunoglobulin deficiency may include the following definitions: 
  • Agammaglobulinemia (total immunoglobulin G [IgG] < 200 mg/dL) 
  • Persistent hypogammaglobulinemia (total IgG < 400 mg/dL, or at least 2 standard deviations below normal, on at least 2 occasions)  
  • Absence of B lymphocytes 
• Inability to mount an adequate antibody response to inciting antigens may include the following definitions: 
  • Lack of appropriate rise in antibody titer following provocation with a polysaccharide antigen  
  • Lack of appropriate rise in antibody titer following provocation with a protein antigen 

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) should have an established diagnosis of CIDP such as criteria established by the American Academy of Neurology in 1991 or those described in a guideline from the European Federation of Neurological Societies and the Peripheral Nerve Society, published in 2006 and updated in 2010. There is currently no criterion standard set of clinical or electrophysiologic criteria for the diagnosis of CIDP and its variants. 

IVIG treatment in CIDP should be limited to patients who do not respond to initial therapy with prednisone and are experiencing serious clinical worsening. In patients treated for chronic diseases (e.g., CIDP, multifocal motor neuropathy, dermatomyositis), the effect of IVIG is transitory and, therefore, periodic infusions of IVIG are needed to maintain treatment effect. The frequency of transfusions is titrated to the treatment response; typically, biweekly or monthly infusions are needed. 

CODING 
There are CPT and HCPCS codes that describe IVIG and SCIG products:

90283: Immune globulin (IgIV), human, for intravenous use
90284: Immune globulin (SCIg), human, for use in subcutaneous infusions, 100 mg, each
J1459: Injection, immune globulin (Privigen), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1554  Injection, immune globulin (asceniv), 500 mg (effective 04/01/2021)
J1555: Injection, immune globulin (Cuvitru), 100mg
J1556: Injection, immune globulin (Bivigam), 500 mg
J1557: Injection, immune globulin (Gammaplex), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1559: Injection, immune globulin (Hizentra), 100 mg
J1561: Injection, immune globulin (Gamunex-C/Gammaked), non-lyophilized (e.g., liquid), 500 mg
J1562: Injection, immune globulin (Vivaglobin), subcutaneous, 100 mg
J1566: Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg
J1568: Injection, immune globulin (Octagam) intravenous, non-lyophilized (e.g., liquid), 500 mg
J1569: Injection, immune globulin (Gammagard Liquid) intravenous, non-lyophilized (e.g., liquid), 500 mg
J1572: Injection, immune globulin (Flebogamma/Flebogamma DIF), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1575: Injection, immune globulin/hyaluronidase, (Hyqvia), 100 mg immune globulin
J1599: Injection, immune globulin, intravenous, non-lyophilized (e.g., liquid), not otherwise specified, 500 mg

The following CPT drug administration codes would be used for the administration of these products:

96365-96366 for intravenous infusions
96369-96371 for subcutaneous infusions

Benefit Application
BlueCard/National Account Issues
Based on benefits or contract language, intravenous immunoglobulin infusion (IVIg) may be considered either a pharmacy or medical benefit as determined by each individual Plan.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Immunodeficiency States
Primary humoral immunodeficiency deficiencies refer to diseases resulting from impaired antibody production because of a molecular defect intrinsic to B cells or a failure of interactions between B and T cells. Antibody deficiency characteristically leads to recurrent, often severe upper and lower respiratory tract infections. Findings associated with severe primary humoral immunodeficiencies include failure to thrive, chronic diarrhea, recurrent fever, nodular lymphoid hyperplasia in the gut, and hepatosplenomegaly.

Primary Humoral Immune Deficiencies
Clinical Context and Test Purpose
The purpose of intravenous immunoglobulin (IVIG) therapy and subcutaneous immunoglobulin (SCIG) therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with primary humoral immunodeficiency.

The question addressed in this evidence review is: Are IVIG and SCIG therapies effective treatments for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals with primary humoral immunodeficiency.

Interventions
The therapies being considered are IVIG and SCIG. Patients with primary humoral immunodeficiency are actively managed by primary care providers and immunologists in an outpatient setting.

Comparators
The following practice is currently being used to treat primary humoral immunodeficiency: standard of care, which often consists of antibiotics, antiviral drugs, and immunoglobulin therapies.

Outcomes
The general outcomes of interest are overall survival (OS), symptoms, change in disease status, morbid events, functional outcomes, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Clinical Studies
In 2010, the National Advisory Committee on Blood and Blood Products and Canadian Blood Services published guidelines on the use of immunoglobulin therapy for patients with primary immune deficiency; recommendations were based on a systematic review of evidence by a panel of experts.² The search identified three RCTs, several cohort studies, and numerous case series.

Clinical immunologists have questioned whether having a low serum immunoglobulin G (IgG) subclass is a true immunodeficiency disease. The rationale is that low serum IgG subclass levels may be found with more sensitive assays available today, and these individuals may be otherwise healthy.

For individuals with immunodeficiencies, both IVIG and SCIG are effective.^3,4,5 Use of SCIG for the treatment of primary immunodeficiencies was approved by the Food and Drug Administration based on an open-label, nonrandomized, prospective, multicenter study.³ Generally, many 10% IVIG solutions can be administered subcutaneously or intravenously, but more concentrated products (e.g., 20%) should not be given intravenously. The subcutaneous route is associated with fewer systemic adverse events and provides more stable serum IgG levels. In contrast, SCIG has not been studied as extensively in autoimmune and inflammatory disorders.

Section Summary: Primary Humoral Immune Deficiencies
The evidence for the use of IVIG and SCIG therapy in primary humoral immune deficiencies consists of multiple RCTs and noncomparative studies. The literature was summarized in a series of evidence-based guidelines (102 studies) initiated by the Canadian Blood Services and the National Advisory Committee on Blood and Blood Products.

Hematopoietic Cell Transplantation (Prophylaxis)
HCT is the intravenous infusion of hematopoietic stem and progenitor cells designed to establish marrow and immune function in patients with various acquired and inherited malignant and nonmalignant disorders.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are undergoing HCT.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals who are undergoing HCT.

Interventions
The therapy being considered is IVIG therapy. Patients who are undergoing HCT are actively managed by hematopoietic transplant specialists in an inpatient setting.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are disease-specific survival (DSS), symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Systematic Reviews
A systematic review and meta-analysis by Raanani et al. (2009) included 30 trials with 4223 patients undergoing HCT.⁶ There was no difference in all-cause mortality between IVIG and cytomegalovirus-IVIG compared with controls (relative risk [RR], 0.99; 95% confidence interval [CI], 0.88 to 1.12; RR = 0.86; 95% CI, 0.63 to 1.16, respectively). There was no difference in clinically documented infections with IVIG compared with control (RR = 1.00; 95% CI, 0.90 to 1.10). Reviewers concluded that routine IVIG prophylaxis in patients undergoing HCT was not associated with survival benefit or reduction in infection and therefore routine use of IVIG prophylaxis in patients undergoing HCT was not recommended.

Randomized Controlled Trials
The initial use of immunoglobulin for prophylaxis in HCT was based on the RCT by Sullivan et al. (1990) in 369 patients undergoing HCT.⁷ The trial showed that neither survival nor risk of relapse was altered by IVIG. However, IVIG treatment was associated with a reduction in the incidence of acute graft-versus-host disease compared with controls (51% vs. 34%) and deaths due to transplant-related causes after transplantation of human leukocyte antigen-identical marrow (46% vs 30%). There were many methodologic flaws in the trial, including a lack of control for type I error for multiple comparisons, the inclusion of a heterogeneous group of patients, and a lack of a placebo control. Subsequent to this pivotal trial, multiple trials have been conducted and systematic reviews have assessed the efficacy of immunoglobulin prophylaxis in HCT to prevent infection and prolong survival.

Section Summary: HCT (Prophylaxis)
The evidence for IVIG for routine prophylaxis of infection in HCT consists of multiple RCTs. The most recent systematic review and meta-analysis published in 2009 included 30 trials and concluded that routine IVIG prophylaxis in patients undergoing HCT was not associated with survival benefit or reduction in infection.

Acute Antibody-Mediated Rejection After Solid Organ Transplant
Acute rejection after transplant can be broadly divided into two categories: the more common acute cellular rejection related to activation of T cells, and the less common acute ABMR related to the presence of antidonor antibodies. Acute ABMR is an entity now better defined and often detected earlier in the clinical course, based on the recognition of characteristic histologic findings, positive C4d staining, and the detection of donor-specific antibodies.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are at risk of acute ABMR after a solid organ transplant or who have acute ABMR after solid organ transplant.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant populations of interest are individuals who are at risk of acute ABMR after a solid organ transplant or who have acute ABMR after a solid organ transplant.

Interventions
The therapy being considered is IVIG therapy. Patients who are at risk of acute ABMR after a solid organ transplant or who have acute ABMR after a solid organ transplant are actively managed by organ transplant surgeons and specialists in an inpatient setting.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are DSSl, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Follow-up at two years is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Prophylaxis
The risk of ABMR is related to the presence of preformed alloantibodies in the recipient due to prior blood transfusions, transplants, or pregnancies. The presence of alloantibodies is assessed using a panel reactive antibody (PRA) screen. Those with a PRA screen greater than 20% are referred to as “sensitized,” and these patients often have prolonged waiting times to identify a compatible donor. Recipients of ABO mismatched donor organs are also at risk of ABMR.

Randomized Controlled Trials
In the National Institutes of Health-sponsored IG02 study, 101 adults with a PRA screen of 50% or higher were randomized to IVIG 2 g/kg monthly for 4 months or placebo.⁸If transplanted, additional infusions were given at 12 and 24 months. Treatment with IVIG therapy resulted in significant reductions in PRA levels compared with placebo (35% vs 17%). Seven graft failures occurred (4 IVIG, 3 placebo) among adherent patients with similar 2-year graft survival rates (80% IVIG, 75% placebo). The investigators concluded that IVIG therapy was better than a placebo in reducing anti-human leukocyte antigen antibody levels and improving transplantation rates in highly sensitized patients with end-stage renal disease. In a follow-up study, the combination of high-dose IVIG and B-cell depletion therapy reduced PRA from 77% to 44% at the time of transplantation.⁹

Nonrandomized Studies
More recent studies have failed to show a reduction in PRA levels, specifically in patients with PRA greater than 80%.^10,11,12 Nonrandomized clinical observations have suggested that a combination of plasmapheresis plus low-dose IVIG and interleukin-2 blockade or rabbit anti-thymocyte globulin for induction was associated with improved patient survival compared with chronic dialysis for the treatment of sensitized patients.^13,14,15

Subsection Summary: Prophylaxis for Acute ABMR After Solid Organ Transplant
The evidence for the use of IVIG for prophylaxis in patients with high PRA levels prior to solid organ transplant consists of multiple RCTs and noncomparative observational studies. RCTs have shown conflicting results that prophylaxis with IVIG in patients with high PRA levels prior to solid organ transplant leads to a significant reduction in PRA levels.

Treatment
Systematic Reviews
Most studies of IVIG treatment for ABMR are retrospective case series from single-institutions. A systematic review by Roberts et al. (2012) of treatments for acute ABMR in renal allografts identified 10,388 citations but only 5 small RCTs, none of which addressed theuse of IVIG in the treatment of ABMR.¹⁶ The RCT by Casadei et al. (2011) demonstrated that IVIG therapy is effective for the treatment of steroid-resistant rejection;¹⁷ however, it should be noted that IVIG was ineligible for inclusion in the Roberts review because 83% of the patients had Banff 1 (pure cellular) rejection on biopsy.¹⁶ According to Roberts et al. (2012), the evidence to support the use of IVIG to treat ABMR is very low (GRADE criteria).

Section Summary: Treatment of Acute ABMR After Solid Organ Transplant
The evidence for the use of IVIG in ABMR consists of retrospective case series. According to a 2012 systematic review, the evidence for IVIG treatment of ABMR is very low (GRADE criteria).

Chronic Lymphocytic Leukemia
CLL is a disorder characterized by progressive accumulation of functionally incompetent lymphocytes and most patients develop hypogammaglobulinemia at some point in the course of their disease. Patients experiencing recurrent bacterial infections associated with hypogammaglobulinemia are likely to benefit from monthly infusions of IVIG.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who have CLL with recurrent bacterial infections associated with hypogammaglobulinemia.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals who have CLL with recurrent bacterial infections associated with hypogammaglobulinemia.

Interventions
The therapy being considered is IVIG therapy. Patients who have CLL with recurrent bacterial infections associated with hypogammaglobulinemia are actively managed by oncologists in an inpatient setting.

Comparators
The following practice is currently being used to treat CLL: standard of care.

Outcomes
The general outcomes of interest are OS, symptoms, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12 and24 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Randomized Controlled Trials
Multiple trials and a meta-analysis comparing IVIG with placebo have shown decreased bacterial infections but not decreased mortality.^{18,19,20,21,22,23} Use of IVIG has not been directly compared with prophylactic antimicrobials. The randomized trials of prophylactic IVIG found that patients who receive IVIG have a decreased incidence of minor and moderate, but not major, bacterial infections. Treatment with IVIG has not been shown to increase the QOL or survival. The largest study was a multicenter randomized trial in 84 patients with CLL who were at increased risk of bacterial infection due to hypogammaglobulinemia, a history of infection, or both.¹⁸ Although minor or moderate bacterial infections were significantly less common in patients receiving IVIG, there was no impact on the incidence of major infections, mortality, or nonbacterial infections.

Section Summary: CLL
The evidence for the use of IVIG therapy for prophylaxis of infection in CLL consists of multiple RCTs that have generally shown reductions in rates of minor and moderate, but not major, bacterial infections. No benefit in QOL and mortality has been shown.

INFECTIONS
HIV-Infected Children
Prevention of opportunistic infections remains a critical component of care for HIV-infected children even though the availability of combination antiretroviral therapies has substantially and dramatically decreased AIDS-related opportunistic infections and deaths.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in children who have HIV infection and recurrent bacterial infections associated with hypogammaglobulinemia.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are children with HIV infection and recurrent bacterial infections associated with hypogammaglobulinemia.

Interventions
The therapy being considered is IVIG therapy. HIV-infected children with recurrent bacterial infections associated with hypogammaglobulinemia are actively managed by infectious disease specialists and primary care providers in an outpatient setting.

Comparators
The following practice is currently being used to treat HIV-infected children: standard of care.

Outcomes
The general outcomes of interest are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 18 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Randomized Controlled Trials
A 1991 double-blind RCT allocated 372 HIV-infected children to IVIG or placebo every 28 days.²⁴ The median length of follow-up was 17 months. Results were stratified by CD4-positive counts (≥ 0.2×10⁹/L or < 0.2×10⁹/L). After 24 months, for children with CD4-positive counts of 0.2×10⁹/L or greater, IVIG treatment compared with placebo significantly increased infection-free rates (67% vs 48% respectively; p < 0.05); reduced overall the number of serious and minor bacterial infections (RR = 0.68; p < 0.05); and reduced the number of hospitalizations for acute care (RR = 0.65; p < 0.05). The effect was less marked in children with CD4-positive counts less than 0.2×10⁹/L.

Guidelines
Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children have recommended IVIG to prevent serious bacterial infections in HIV-infected children who have IgG levels less than 400 mg/dL.²⁵ The guidelines for the prevention and treatment of serious opportunistic infections in HIV-infected adults and adolescents do not give such recommendations.²⁶

Subsection Summary: HIV-Infected Children
The evidence for the use of IVIG for prophylaxis of opportunistic infections in children with HIV consists of an RCT that showed a reduction in serious and minor bacterial infections and hospitalization. A reduction in mortality has not yet been demonstrated.

Neonatal Sepsis
Preterm and low birth weight infants are prone to infection because of an immature immune system as well as increased exposure to nosocomial pathogens.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are preterm and low birth weight infants and at risk for sepsis or who have sepsis.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant populations of interest are infants who are preterm, low birth weight, and at risk for sepsis or who have sepsis.

Interventions
The therapy being considered is IVIG therapy. Infants who are preterm, low birth weight, and at risk for or who have sepsis are actively managed by neonatologists and pediatricians in an inpatient setting.

Comparators
The following practice is currently being used to treat preterm, low birth weight, infants at risk for sepsis or who have sepsis: standard of care.

Outcomes
The general outcomes of interest are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Prophylaxis of Neonatal Sepsis
A Cochrane review by Ohlsson and Lacy (2013) assessed IVIG for the prevention of infection in preterm and/or low birth weight infants.²⁷ Reviewers identified 19 RCTs that compared IVIG against placebo or no intervention for approximately 5,000 preterm (< 37 weeks of gestational age) and/or low birth weight (< 2,500 g) infants. Five of the 19 studies were considered to be high-quality; the other had potential biases (e.g., lack of caregiver blinding in 10 studies). In a meta-analysis of 10 studies, IVIG was associated with a statistically significant reduction in sepsis (³1 episodes; RR = 0.85; 95% CI, 0.75 to 0.98). Moreover, a meta-analysis of 16 studies showed a significant reduction in serious infection (≥ 1 episodes) with IVIG (RR = 0.82; 95% CI, 0.74 to 0.92). However, IVIG was not associated with a significant reduction in mortality. Meta-analysis of 15 studies that reported all-cause mortality found a RR of 0.89 (95% CI, 0.75 to 1.05), and meta-analysis of 10 studies that reported mortality due to infection found a RR of 0.83 (95% CI, 0.56 to 1.22). Reviewers noted that a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection without a reduction in other clinically important outcomes, including mortality, were of marginal clinical importance. No major adverse events related to IVIG administration were reported.

Subsection Summary: Prophylaxis of Neonatal Sepsis
The evidence for the use of IVIG therapy for prophylaxis of infection in preterm and/or low birth weight infants consists of multiple RCTs that have generally shown reductions in the rates of sepsis but no benefit in mortality. A meta-analysis of ten studies assessing the use of IVIG for prophylaxis of infection in preterm and/or low birth weight infants concluded that a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection without reduction in other clinically important outcomes, including mortality, was of marginal clinical importance.

Treatment of Neonatal Sepsis
Systematic Reviews
A Cochrane review by Ohlsson and Lacy (2015) identified 9 trials that compared IVIG with placebo or standard care in neonates (< 28 days old) with suspected or confirmed infection.²⁸ Studies included a total of 3,973 infants; the largest trial had a sample size of 3,493 and contributed 90% of the data. Meta-analysis of all 9 trials found no statistically significant difference in mortality rates with IVIG vs the control therapy (RR = 0.95; 95% CI, 0.80 to 1.13). Meta-analysis of 3 trials found that IVIG significantly reduced the length of the hospital stay compared with a control intervention (mean difference [MD], -4.08; 95% CI, -6.47 to -1.69). Results were not pooled for other outcomes.

Randomized Controlled Trials
The trial with a large sample size was published by the International Neonatal Immunotherapy Study group (2011); it was conducted in 9 countries.²⁹ Infants receiving antibiotics for suspected or confirmed serious infection were randomized to 2 infusions of IVIG at a dose of 500 mg/kg of body weight (n = 1,759) or a matching volume of placebo (n = 1,734). Infusions were given 48 hours apart. The primary study outcome was the rate of death or major disability (according to predefined criteria) at age two years. By age 2, 686 (39%) of 1,759 children in the IVIG group had died or suffered major disability compared with 677 (39%) of 1734 children in the placebo group (RR = 1.00; 95% CI, 0.92 to 1.08). There were also no statistically significant differences in the primary outcome when prespecified subgroups (e.g., birthweight, gestational age at birth, sex) were examined. Moreover, there were no statistically significant differences between groups in secondary outcomes, including rates of subsequent sepsis episodes. The number of reported adverse events was 12 in the IVIG group (including 2 deaths) vs 10 in the placebo group (including 4 deaths).

Section Summary: Treatment of Neonatal Sepsis
The evidence for the use of IVIG treatment for suspected or confirmed infection in neonates consists of multiple RCTs. The largest RCTs in 3,493 neonates showed that there was no difference in the rates of death or major disability between IVIG-treated neonates and placebo-treated neonates. A meta-analysis (nine studies) also did not find a significant difference in mortality rates or major disability with IVIG vs control.

Sepsis in Adults
Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in adults with sepsis.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest is adults with sepsis.

Interventions
The therapy being considered is IVIG therapy. Adults with sepsis are actively managed by intensivists and infectious disease specialists in an inpatient setting.

Comparators
The following practice is currently being used to treat adults with sepsis: standard of care.

Outcomes
The general outcomes of interest are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Systematic Reviews
A meta-analysis by Busani et al. (2016), which pooled 18 RCTs, showed that the use of IVIG reduced the mortality risk of septic patients by half (odds ratio [OR] = 0.50; 95% CI, 0.34 to 0.71).³⁰ However, there was a preponderance of small low-quality studies in the evidence base, which was further complicated by heterogeneous dosing regimens and types of IVIG preparations used across studies that were conducted over a long time horizon. Reviewers concluded that the evidence did not support the widespread useof IVIG as adjunctive therapy for sepsis in adults.

Section Summary: Sepsis in Adults
The evidence for the use of IVIG treatment for sepsis in adults consists of a meta-analysis of 18 RCTs. Though the meta-analysis demonstrated reductions in mortality risk, most studies included were small, of low quality, and employed heterogeneous dosing regimens and types of IVIG preparations.

Severe Anemia Associated With Human Parvovirus B19
Human parvovirus B19 is a common single-stranded DNA virus. Infections are usually mild or asymptomatic and do not require treatment. In some cases, the infection can lead to sufficiently severe complications such as transient aplastic crisis, in which case treatment is indicated and may be lifesaving.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with severe anemia associated with human parvovirus B19.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for human parvovirus infection?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals with severe anemia associated with human parvovirus B19.

Interventions
The therapy being considered is IVIG therapy. Patients with severe anemia associated with human parvovirus B19 are actively managed by primary care providers and infectious disease specialists in an outpatient setting.

Comparators
The following practice is currently being used to treat severe anemia associated with human parvovirus B19 virus: standard of care.

Outcomes
The general outcomes of interest are a change in disease status, treatment-related mortality, and treatment-related morbidity. Follow-up at 12 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Case Series
No controlled trials have evaluated IVIG for severe anemia associated with parvovirus B19. Only small case series and case reports are available.^31,32,33 One larger case series, by Crabol et al. (2013), retrospectively reported on 10 patients with documented human parvovirus B19 and pure red cell aplasia.³⁴ Following a mean of 2.7 courses of IVIG treatment, hemoglobin level was corrected in 9 of 10 patients. Four patients had adverse events associated with IVIG (two cases of acute reversible renal failure, two cases of pulmonary edema). In the same article, the authors reported on findings of a literature search in which they identified 123 cases of pure red cell aplasia treated with IVIG (other than the 10 patients in their series). Among 86 (70%) of 123 patients available at 12-month follow-up, hemoglobin was corrected in 36 (42%) patients, and the remaining 50 (58%) patients had persistent anemia.

Section Summary: Severe Anemia Associated With Human Parvovirus B19
The evidence for the use of IVIG treatment for severe anemia associated with human parvovirus B19 consists of case series and case reports. The largest case series (10 patients) showed that IVIG treatment was associated with the correction of anemia in most patients. Controlled trials are lacking.

Toxic Shock Syndrome
Toxic shock syndrome is also called as Streptococcal toxic shock syndrome. Streptococcal toxins induce the release of inflammatory cytokines, which cause capillary leakage and tissue damage resulting in shock, multiorgan failure, and death.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in women with toxic shock syndrome.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for toxic shock syndrome?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are women with toxic shock syndrome.

Interventions
The therapy being considered is IVIG therapy. IVIG is used for the treatment of septic shock syndrome to boost antibody levels via passive immunity. Women with toxic shock syndrome are actively managed by primary care providers in an outpatient clinical setting.

Comparators
The following therapy is currently being used to treat toxic shock syndrome: corticosteroids.

Outcomes
The general outcomes of interest are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Randomized Controlled Trials
The evidence for the use of IVIG treatment for toxic shock syndrome is limited and includes a small RCT³⁵ and multiple observational studies.^36,37,38,39 The RCT by Darenberg et al. (2003) allocated 21 adults with toxic shock syndrome to IVIG or to placebo.³⁵ Mortality rates were 10% and 36%, respectively, but the difference in mortality rates was not statistically significant. Additionally, the trial was originally planned to enroll 120 patients, so it was likely underpowered to detect any significant differences.

Prospective and Retrospective Studies
In a prospective observational study, Linner et al. (2014) compared 23 patients receiving IVIG therapy with 44 patients receiving a placebo.³⁶ The odds for survival were 5.6 for IVIG vs placebo (p = 0.03). The proportion of patients alive at 28 days by treatment was 87% and 50%, respectively. In 2 retrospective studies, 27 patients with toxic shock syndrome treated with IVIG were compared with historical controls.^37,38 While the mortality rate was lower with IVIG than with historical controls, lack of randomization or statistical adjustment of the two groups poses difficulties when interpreting the results. A retrospective study by Shah et al. (2009), which included 192 children with toxic shock syndrome failed to show improvement in outcomes with IVIG.³⁹

Section Summary: Toxic Shock Syndrome
The evidence for the use of IVIG treatment for toxic shock syndrome consists of a small RCT and multiple observational studies. Most studies demonstrated a beneficial effect of treatment on mortality. 

Autoimmune and Inflammatory Conditions 
Idiopathic Thrombocytopenic Purpura 
ITP, also known as primary immune thrombocytopenia, is acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is a more common cause of thrombocytopenia in otherwise asymptomatic adults. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with ITP. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with ITP. 

Interventions 

The therapy being considered is IVIG therapy. Patients with ITP are actively managed by hematologists and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat ITP: corticosteroids. 

Outcomes
The general outcomes of interest are DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes.

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Randomized and Nonrandomized Trials 
In 2007, the National Advisory Committee on Blood and Blood Products and the Canadian Blood Services issued guidelines on the use of IVIG for hematologic conditions, including ITP, based on 6 RCTs and 1 nonrandomized trial of IVIG for adult ITP.⁴⁰ Three of the trials compared IVIG with corticosteroids, and four trials evaluated different doses of IVIG. None compared IVIG with no therapy. The largest trial, by Godeau et al. (2002), compared IVIG with corticosteroids in 122 patients with severe acute ITP.⁴¹ The primary outcome, the mean number of days with a platelet count greater than 50´10⁹/L at day 21, was significantly greater in the IVIG group than in the high-dose methylprednisolone group. Two other trials, 1 nonrandomized (IVIG vs corticosteroids)⁴² and 1 randomized (IVIG alone vs oral prednisone alone vs IVIG plus oral prednisone)⁴³ found no differences in platelet counts greater than 50´10⁹/L at 48 hours or in response rates between groups, respectively. 

Section Summary: ITP 
The evidence for the use of IVIG treatment for ITP consists of multiple RCTs and noncomparative studies. The largest RCT (122 patients) showed IVIG treatment increased platelet levels to a greater extent than corticosteroids. However, one RCT trial found no difference in platelet counts compared with corticosteroids.

Guillain-Barré Syndrome
GBS is a heterogeneous condition with several variant forms and encapsulates many acute immune-mediated polyneuropathies. It is characterized by a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with GBS. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with GBS. 

Interventions 
The therapy being considered is IVIG therapy. Patients with GBS are actively managed by neurologists and primary care providers primarily in an acute care setting.

Comparators 
The following therapies are currently being used to treat GBS: plasma exchange, immunoadsorption, and supportive care. 

Outcomes 
The general outcomes of interest are OS,DSS al, symptoms, change in disease status, morbid events, and treatment-related mortality and morbidity. Follow-up at four weeks is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
An updated Cochrane review by Hughes et al. (2014) evaluated results from randomized trials of immunotherapy for GBS.⁴⁴ Reviewers identified 12 randomized trials; none was placebo-controlled. Seven trials compared IVIG with plasma exchange, three trials compared IVIG with supportive treatment only, two trials compared plasma exchange, and two others compared IVIG with immunoabsorption (one compared IVIG plus immunoabsorption with immunoabsorption only). Four trials included adults only, five included children only, one included both, and two included adults and possibly children. The primary outcome of the review was change in disability level (using a 7-grade disability scale) after four weeks. A pooled analysis of 7 trials comparing IVIG with plasma exchange did not find significant differences between groups in change in the number of disability grades at 4 weeks (MD = -0.02; 95% CI, -0.25 to 0.20). There were also no significant differences in other outcome measures for IVIG vs plasma exchange (e.g., number of patients who improved by ³1 grades). There were insufficient data to pool results for comparisons of IVIG with other interventions or for subgroup analysis by age. However, patients assigned to IVIG were significantly less likely to discontinue treatment than patients assigned to plasma exchange (RR = 0.14; 95% CI, 0.05 to 0.36). 

Most trials in this review had small sample sizes. The largest was a 1997 multicenter, randomized trial of 383 adults that compared IVIG, plasma exchange, and combination IVIG plus plasma exchange.⁴⁵ Trial objectives were to establish that IVIG is equivalent or superior to plasma exchange and to establish that plasma exchange followed by IVIG is superior to a single treatment. Noninferiority was defined as no more than a 0.5-grade difference in change in disability grade at four weeks. At 4 weeks, the difference in improvement between the IVIG group and plasma exchange group was 0.09 grade (95% CI, -0.23 to 0.42); this met the predefined criterion for equivalence of these treatments. Differences were 0.29 grade (95% CI, -0.04 to 0.63) between the IVIG plus plasma exchange group and the IVIG only group, and 0.20 grade (95% CI, -0.14 to 0.54) between the IVIG plus plasma exchange group and the plasma exchange only group. Thus, neither combined treatment group proved superior to either treatment alone. 

Miller Fisher syndrome is a variant of GBS characterized by impairment of eye movements (ophthalmoplegia), incoordination (ataxia), and loss of tendon reflexes (areflexia). A Cochrane review by Overell et al. (2007) evaluated acute immunomodulatory therapies in Miller Fisher syndrome or its variants.⁴⁶ No RCTs were identified. 

Section Summary: GBS 
The evidence for IVIG treatment for GBS patients consists of multiple RCTs that compared IVIG therapy with other modalities such as plasma exchange and immunoabsorption but not placebo. A Cochrane meta-analysis of seven trials comparing IVIG therapy with plasma exchange did not find a significant difference in disability scores. The largest RCT (383 GBS patients) showed noninferiority between IVIG and plasma exchange. 

Kawasaki Disease 
Kawasaki disease is among the most common vasculitides of childhood; it is characterized by fever and manifestations of acute inflammation lasting for an average of 12 days without therapy. It is typically self-limiting but may cause cardiovascular complications, particularly coronary artery aneurysms, which can lead to coronary occlusion and cardiac ischemia ultimately leading to significant morbidity and even death. Therefore, early treatment is essential. Although the mechanism of action of IVIG is not understood, its use early in the course of the disease has reduced the prevalence of coronary artery abnormalities. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Kawasaki disease. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with Kawasaki disease. 

Interventions 
The therapy being considered is IVIG therapy. Patients with Kawasaki disease are actively managed by multiple specialists and primary care providers primarily in an acute care setting.

Comparators 
The following practice is currently being used to treat Kawasaki disease: standard of care. 

Outcomes 
The general outcomes of interest are DSS, change in disease status, and treatment-related mortality and morbidity. Follow-up at 30 days is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
Multiple RCTs and meta-analysis, have demonstrated the efficacy of IVIG in preventing cardiac consequences of Kawasaki disease in children. A Cochrane review of RCTs by Oates-Whitehead et al. (2003) identified 59 trials in the initial search and selected 16 trials for meta-analysis using RR for dichotomous data or weighted MD for continuous data.⁴⁷ Results showed a significant decrease in new coronary artery abnormalities in favor of IVIG compared with placebo at 30 days (RR = 0.74; 95% CI, 0.61 to 0.90). Reviewers concluded that children fulfilling the diagnostic criteria for Kawasaki disease should be treated with IVIG (2 g/kg single dose) within 10 days of onset of symptoms 

Section Summary: Kawasaki Disease 
The evidence for the use of IVIG treatment for Kawasaki disease consists of multiple RCTs and noncomparative studies. A Cochrane meta-analysis of 16 trials comparing IVIG with placebo in children with Kawasaki disease showed that treatment with IVIG decreased the incidence of new coronary artery abnormalities. 

Granulomatosis With Polyangiitis (Wegener Granulomatosis) 
Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with granulomatosis with polyangiitis (Wegener granulomatosis). 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with granulomatosis with polyangiitis (Wegener granulomatosis). 

Interventions 
The therapy being considered is IVIG therapy for maintenance therapy. Patients with granulomatosis with polyangiitis (Wegener granulomatosis) are actively managed by rheumatologists, nephrologists and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat granulomatosis with polyangiitis: standard of care. 

Outcomes 
The general outcomes of interest are DSS, change in disease status, and treatment-related mortality and morbidity. Follow-up at three months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
The success of IVIG therapy for Kawasaki disease led to a study of IVIG therapy for other vasculitides such as Wegener granulomatosis. A Cochrane review by Fortin et al. (2013) identified 1 RCT on IVIG for Wegener granulomatosis.⁴⁸ This trial, published by Jayne et al. (2000), compared single course IVIG (n = 17) with placebo (n = 17) and found significantly more responders in the IVIG treatment group at 3 months but no significant differences after 3 months or in the frequency of relapse or use of other medications.⁴⁹ 

Section Summary: Granulomatosis With Polyangiitis (Wegener Granulomatosis) 
A 2013 Cochrane review identified 1 RCT on IVIG for Wegener granulomatosis. This small trial found significantly more responders in the IVIG treatment group at three months but no significant differences after three months, or in the frequency of relapse or use of other medications. 

Chronic Inflammatory Demyelinating Polyneuropathy 
CIDP is an acquired neurologic disorder characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is caused by damage to the myelin sheath of the peripheral nerves. CIDP is difficult to diagnose due to its heterogeneous presentation (both clinical and electrophysiological). 

Clinical Context and Test Purpose 
The purpose of IVIG and SCIG therapies is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with CIDP. 

The question addressed in this evidence review is: Are IVIG and SCIG therapies effective treatments for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with CIDP. 

Interventions 
The therapies being considered are IVIG and SCIG. Patients with CIDP are actively managed by multiple specialists and primary care providers in an outpatient setting after initial treatment. 

Comparators
The following therapies are currently being used to treat CIDP: plasma exchange, immunoadsorption, and supportive care. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Follow-up as long as 48 weeks is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

IVIG Therapy 
Systematic Reviews 
Eftimov et al. (2013) published a Cochrane review of RCTs on IVIG for treating CIDP.⁵⁰ Reviewers identified 8 RCTs that enrolled 332 patients with definite or probable CIDP and that compared IVIG with placebo, corticosteroid, or plasma exchange. Three trials compared IVIG with another active treatment,^51,52,53 and the other 5 were placebo-controlled (n = 235).^{54,55,56,57,58} The primary trial outcome was the proportion of participants with a significant improvement in disability within six weeks of starting treatment. Studies used a variety of disability measures. When possible, reviewers transformed the data on disability into a modified 6-point Rankin Scale for disability. Data from the five placebo-controlled randomized trials were pooled. The pooled RR for improvement in the IVIG group compared with the placebo group was 2.40 (95% CI, 1.72 to 3.36; p < 0.001). When data were pooled from 3 studies on IVIG vs placebo in which the disability measures could be converted to the Rankin Scale, the RR was similar (2.40) but not statistically significant (95% CI, 0.98 to 5.83; p = 0.054). Pooled analyses of data from these three placebo-controlled trials found a statistically higher rate of any adverse event with IVIG, but no serious adverse events. Data from studies comparing IVIG with active treatment were not pooled due to differences in comparators. Limitations of the meta-analysis included the use of different disability scales and varying definitions of clinical response.

An evidence-based guideline on IVIG for treating neuromuscular disorders, prepared by Patwa et al. (2012) for the American Academy of Neurology (AAN), stated that IVIG should be offered for long-term treatment of CIDP.⁵⁹

Randomized Controlled Trials
The ICE study reported by Hughes et al. (2008), the largest included in the meta-analysis, was a double-blind, multicenter trial that randomized 117 patients to IVIG or placebo.⁵⁸ The primary outcome measure was the proportion of patients showing clinically meaningful reductions in disability at week 24. Results showed that the proportion of patients meeting the primary endpoint was significantly greater with IVIG treatment (54%) than with placebo (21%), with an absolute difference of 33.5% (95% CI, 15.4% to 51.7%). In the 24-week extension phase, 57 patients who received IVIG in the randomized phase were rerandomized to IVIG or placebo. Relapse rates were significantly lower for patients treated with IVIG (13% vs 45%; hazard ratio, 0.19; 95% CI, 0.05 to 0.70). Benefits of IVIG treatment extended to as long as 48 weeks with maintenance treatments of 1 g/kg every 3 weeks.

Subsection Summary: IVIG Therapy for CIDP
The evidence for the use of IVIG treatment for CIDP consists of multiple RCTs. The largest trial (117 patients) found that IVIG treatment led to clinically meaningful reductions in disability compared with placebo. A Cochrane meta-analysis of five RCTs comparing IVIG with placebo found that IVIG reduced disability. 

SCIG Therapy 
In the randomized, double-blind, placebo-controlled, phase 3 PATH trial, van Schaik et al. (2018) studied the relapse rates in 172 patients with CIDP given SCIG and placebo.⁶⁰ Patients were randomized in a 1:1:1 ratio to a placebo group (n = 57 [33%]), a low-dose group (n = 57 [33%]), and a high-dose group (n = 57 [33%]). The trial found that both SCIG doses were effective and well-tolerated, suggesting that can be used as maintenance treatment for CIDP. Seventy-seven patients withdrew from the trial due to relapse- or other reasons: 36 (63%; 95% CI, 50% to 74%) placebo patients, 22 (39%; 95% CI, 27% to 52) low-dose SCIG patients, and 19 (33%; 95% CI, [22% to 46) high-dose patients (p < 0.001). The trial was limited by missing patient data and inadequate follow-up of those who withdrew. 

One crossover RCT comparing IVIG and SCIG for CIDP was identified; this trial by Markvardsen et al. (2017) included 20 patients.⁶¹ Patients underwent 10 weeks of treatment with SCIG and IVIG, in random order, for a total intervention duration of 20 weeks. The primary efficacy outcome was change in isokinetic muscle strength. Fourteen (20%) of 20 patients completed the trial. Isokinetic muscle strength increased by 7.4% with SCIG and 14% with IVIG; the difference between groups was not statistically significant. Conclusions about the relative efficacy of SCIG and IVIG cannot be drawn from this trial due to the small sample size, high dropout rate, short-term follow-up, and the crossover design without a washout period. 

Section Summary: SCIG Therapy for CIDP 
Only 1 RCT has directly compared SCIG with IVIG in patients who had CIDP and conclusions about the relative efficacy of the treatments cannot be drawn due to methodologic limitations (e.g., 45% of patients withdrew from the trial). Another RCT demonstrated that the use of SCIG for the maintenance of CIDP might be effective, with relatively low adverse events, but this trial also had a number of limitations (e.g., small sample, 30% dropout rate). Additional direct comparisons, particularly in parallel-group RCTs, are needed. 

Multifocal Motor Neuropathy 
Multifocal motor neuropathy (MMN is a rare neuropathy characterized by progressive asymmetric weakness and atrophy without sensory abnormalities, a presentation similar to that of motor neuron disease. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with MMN. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with MMN. 

Interventions 
The therapy being considered is IVIG therapy. Patients with MMN are actively managed by neurologists and primary care providers in an outpatient setting. 

Comparators
The following practice is currently being used to treat MMN: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. A follow-up at four months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
Van Schaik et al. (2005) included 4 RCTs (total n = 34 patients) in a meta-analysis to assess the efficacy and safety of IVIG in MMN.⁶² Strength improved in 78% of patients treated with IVIG vs 4% in placebo-treated patients. Disability was reduced by 39% and 11%, respectively (p = NS). Mild, transient side effects were reported in 71% of IVIG-treated patients. Serious side effects were not encountered. 

Randomized Controlled Trials 
The benefit of IVIG for MMN has been evaluated in 4 RCTs (total n = 53 patients).^63,64,65,66 The largest of the 4 RCTs randomized 19 patients with MMN with persistent conduction block to IVIG or placebo. Response to treatment was assessed using the Medical Research Council score in 28 muscles; a responder was defined as at least 1 more Medical Research Council point in 2 affected muscles plus 1 point less in 2 activities of daily life compared with baseline. At four months, seven of nine patients who received IVIG responded compared with two of nine patients treated with placebo. 

Section Summary: MMN 
The evidence for use IVIG therapy for MMN consists of multiple RCTs. A Cochrane meta-analysis of 4 RCTs comparing IVIG with placebo found that IVIG treatment led to significant improvements in muscle strength but not reductions in disability levels. The largest trial of 19 patients found that IVIG treatment with IVIG improved muscle strength compared with the placebo. 

Eaton-Lambert Myasthenic Syndrome 
Eaton-Lambert myasthenic syndrome is an autoimmune disease with antibodies directed against the neuromuscular junction. Patients have muscle weakness of the lower extremities, autonomic dysfunction, and extra-ocular muscle impairment. This is a paraneoplastic syndrome associated most commonly with small-cell lung cancer. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Eaton-Lambert myasthenic syndrome. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with Eaton-Lambert myasthenic syndrome.

Interventions 
The therapy being considered is IVIG therapy. Patients with Eaton-Lambert myasthenic syndrome are actively managed by neurologists and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat Eaton-Lambert myasthenic syndrome: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Randomized Controlled Trials 
A crossover RCT by Bain et al. (1996) evaluated 9 patients treated with IVIG therapy (1 g/kg/d for 2 days) or placebo showed statistically significant improvements in serial measurements of limb, respiratory, and bulbar muscle strength associated with IVIG treatment, and a nonsignificant improvement in the resting compound muscle action potential amplitude.⁶⁷ 

A number of noncomparative studies have substantiated clinical benefits.^68,69,70,71 

Section Summary: Eaton-Lambert Myasthenic Syndrome 
The evidence for IVIG therapy for Eaton-Lambert myasthenic syndrome consists of a single RCT and multiple noncomparative studies. In the RCT (nine patients), IVIG treatment demonstrated significant improvement in muscle strength compared with the placebo. 

Neuromyelitis Optica 
NMO is an inflammatory disorder of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and spinal cord. Previously considered a variant of multiple sclerosis, it is now recognized as a distinct clinical entity. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with NMO. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with NMO. 

Interventions 
The therapy being considered is IVIG therapy. Patients with NMO are actively managed by ophthalmologists, neurologists and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat NMO: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at two years is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Retrospective Studies 
A retrospective review by Elsone et al. (2014) of 10 patients treated with IVIG for acute relapses after lack of response to steroids with or without plasma exchange showed improvement in about 50% of patients.⁷² A case series by Magraner et al. (2013) assessed 9 Spanish NMO patients and yielded positive results using bimonthly IVIG treatment (0.7 g/kg body weight per day for 3 days) for up to 2 years.⁷³ 

Section Summary: NMO 
The evidence for IVIG therapy for NMO consists of multiple noncomparative studies. The results of these studies have shown that IVIG treatment may benefit patients who are refractory to first-line treatment. 

Severe Refractory Myasthenia Gravis or Myasthenic Exacerbation 
Myasthenia gravis is a relatively rare autoimmune disorder in which antibodies form against acetylcholine nicotinic postsynaptic receptors at the neuromuscular junction of skeletal muscles resulting in characteristic patterns of progressively reduced muscle strength with repeated use and recovery of muscle strength after a period of rest. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with severe refractory myasthenia gravis or myasthenic exacerbation.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant populations of interest are individuals with severe refractory myasthenia gravis or myasthenic exacerbation. 

Interventions 
The therapy being considered is IVIG therapy. Patients with severe refractory myasthenia gravis or myasthenic exacerbation are actively managed by neurologists and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat myasthenia gravis: plasma exchange. 

Outcomes
The general outcomes of interest are OS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Treatment of two weeks is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication.

Systematic Reviews
A Cochrane review by Gadjos et al. (2012) assessed IVIG therapy for acute exacerbations or for chronic long-term myasthenia gravis.⁷⁴ Reviewers identified seven RCTs including an unpublished trial, all of which investigated short-term benefit. The trials varied in inclusion criteria, comparator interventions, and outcome measures and, thus, trial findings were not pooled. Five trials evaluated IVIG for treating myasthenia gravis worsening or exacerbation, and two evaluated IVIG for treatment of moderate or severe myasthenia gravis. Several trials were small, with insufficient statistical power. Reviewers concluded that there was some evidence for efficacy in exacerbations of myasthenia gravis, and that evidence for treating chronic myasthenia gravis was insufficient to form conclusions about efficacy. 

Randomized Controlled Trials 
Zinman et al. (2007) conducted the only RCT that compared IVIG with placebo in 51 patients who had myasthenia gravis with progressive weakness.⁷⁵ The primary outcome measure was the difference between arms in the Quantitative Myasthenia Gravis Score for Disease Severity from baseline to days 14 and 28. In IVIG-treated patients, a clinically meaningful improvement in Quantitative Myasthenia Gravis Score for Disease Severity was observed at day 14 and persisted at day 28. The greatest improvement occurred in patients with more severe disease as defined by a Quantitative Myasthenia Gravis Score for Disease Severity greater than 10.5. 

Other RCTs either compared IVIG with plasma exchange or compared two doses of IVIG. Barth et al. (2011) compared IVIG with plasma exchange in 84 patients with moderate-to-severe myasthenia gravis.⁷⁶ The trial did not find a statistically significant difference in the efficacy between treatments. Gajdos et al. (2005) compared 2 doses of IVIG (1 g and 2 g/kg) in 170 patients with acute exacerbation of myasthenia gravis.⁷⁷ Mean improvement in the myasthenic muscular scores did not differ significantly between doses after two weeks. Gajdos et al. (1997) compared IVIG with plasma exchange in 87 patients with myasthenia gravis exacerbations.⁷⁸ The trial also did not find a statistically significant difference in the efficacy between the two treatments; however, the trial did report that IVIG was better tolerated. Nine patients experienced adverse events (eight in the plasma exchange group, one in the IVIG group). 

Section Summary: Severe Refractory Myasthenia Gravis or Myasthenic Exacerbation 
The evidence for IVIG treatment for severe refractory myasthenia gravis or myasthenic exacerbation consists of multiple small trials. The largest trial (51 myasthenia gravis patients) showed a clinically meaningful improvement in disease severity with IVIG compared with placebo. Two other RCTs (n > 80 patients) assessing myasthenia gravis exacerbations showed noninferiority between IVIG and plasma exchange. A Cochrane review evaluating seven RCTs did not pool the results because of study heterogeneity; reviewers concluded that there was limited evidence for efficacy in exacerbations of myasthenia gravis. 

Relapsing-Remitting Multiple Sclerosis
RRMS is an immune-mediated inflammatory disease that attacks and destroys myelinated axons in the central nervous system, resulting in variable degrees of physical disability characterized by symptomatic episodes that occur months or years apart and affect different anatomic locations.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with RRMS. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with RRMS. 

Interventions 
The therapy being considered is IVIG therapy. Patients with RRMS are actively managed by neurologists and primary care providers in an outpatient clinical setting. 

Comparators 
The following practice is currently being used to treat RRMS: standard of care. 

Outcomes 
The general outcomes of interest are OS, DSS, symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Treatment of two weeks is of interest to monitor outcomes. 

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
Based on a technology assessment by Goodin et al. (2002), the AAN recommended the use of interferon beta (type B recommendation) and glatiramer acetate (type A recommendation) for the treatment of RRMS.⁷⁹ The AAN suggested that IVIG was no longer considered a drug of choice for RRMS. 

Section Summary: RRMS
The evidence for the use of IVIG treatment for RRMS consists of multiple RCTs that were summarized in a technology assessment. Since then, multiple new treatments have become available for the treatment of RRMS with demonstrable efficacy and safety. 

Autoimmune Mucocutaneous Blistering Diseases 
Autoimmune mucocutaneous blistering diseases are a group of conditions that manifest with blisters on the skin or mucous membranes and include pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, and linear IgA dermatosis. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with autoimmune mucocutaneous blistering diseases. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with autoimmune mucocutaneous blistering diseases. 

Interventions 
The therapy being considered is IVIG therapy. Patients with autoimmune mucocutaneous blistering diseases are actively managed by specialist care providers in an outpatient setting.

Comparators 
The following practice is currently being used to treat autoimmune mucocutaneous blistering diseases: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
A systematic review by Gurcan et al. (2010) identified 23 studies evaluating IVIG for autoimmune mucocutaneous blistering diseases (1 RCT, 22 case series).⁸⁰ The studies included 260 patients treated with IVIG: 191 patients had pemphigus, and 69 patients had pemphigoid. Of the 260 patients, 245 (94%) improved after IVIG treatment. 

Randomized Controlled Trials
Amagai et al. (2017) evaluated IVIG for bullous pemphigoid in a multicenter, double-blind and placebo-controlled randomized trial that included 56 patients.⁸¹ The IVIG group received 400 mg/kg/d for 5 days and the placebo group received saline for 5 days. The primary endpoint was the Disease Activity Score (DAS) on day 15 (lower score is a better outcome). Mean scores were 19.8 in the IVIG group and 32.3 in the placebo group, but the difference between groups was not statistically significant (p = 0.089). In a post hoc analysis using the DAS on day 1 as a covariate, the DAS was significantly lower in the IVIG group (19.7) than in the placebo group (32.4) at day 15 (p = 0.041). In patients with severe disease, there were significantly lower DAS scores in the IVIG than in the placebo group on days 8, 15, and 22; between-group scores did not differ in patients with mild or moderate disease.

Another RCT by the same research group was published by Amagai et al. (2009); it was multicenter, placebo-controlled and double-blind that included adults with glucocorticoid-resistant pemphigus (defined as a failure to respond to the equivalent of prednisolone ≥ 20 mg/d).⁸² Patients were randomized to a single cycle of IVIG 400 mg/kg/d for 5 days, IVIG 200 mg/kg/d for 5 days or a placebo infusion for 5 days. The primary endpoint was the duration of time that patients could be maintained on the treatment protocol before symptoms required additional treatment (i.e., time to escape protocol). Time to escape protocol was significantly longer for patients in the IVIG 400-mg group than for patients in the placebo group but not between the IVIG 200-mg group and the placebo group. Furthermore, a significant decrease in a pemphigus activity score was detected at all study observation points for patients in the IVIG 400-mg group and at all study observation points after day 15 in the IVIG 200-mg group. The pemphigus activity score did not decrease significantly at any time point in the placebo group.

Section Summary: Autoimmune Mucocutaneous Blistering Diseases 
The evidence for IVIG treatment for autoimmune mucocutaneous blistering diseases consists of two RCTs and multiple noncomparative studies. The RCT in glucocorticoid-resistant pemphigus patients demonstrated that IVIG treatment decreased disease activity and the need for additional treatment compared with placebo. The RCT in patients with bullous pemphigoid found that IVIG was effective in the subgroup of patients with severe disease. A systematic review pooled data of 260 patients across 23 studies and showed improvements in most patients. 

Toxic Epidermal Necrosis and Stevens-Johnson Syndrome 
Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with TEN or SJS. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant populations of interest are individuals with TEN or SJS. 

Interventions 
The therapy being considered is IVIG therapy. Patients with TEN or SJS are actively managed by specialists in an inpatient setting. 

Comparators 
The following practice is currently being used to treat TEN or SJS: standard of care. 

Outcomes 
The general outcomes of interest are DSS, symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes.

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
Several systematic reviews have evaluated the literature on TEN and SJS. More recently, Huang et al. (2016) identified 11 studies evaluating IVIG for TEN or SJS, none of which were RCTs.⁸³ Three of the studies had control groups and two of these included historical controls. IVIG was not found to reduce mortality in TEN or SJS. The pooled standardized mortality ratio in the 10 studies was 1.00 (95% CI, 0.76 to 1.32, p = 0.67). A meta-analysis by Barron et al. (2015) also did not demonstrate a survival advantage of IVIG for TEN and/or SJS.⁸⁴ 

Section Summary: TEN and SJS 
No RCTs identified evaluated IVIG for TEN or SJS. There are several systematic reviews of observational studies, controlled and uncontrolled. A 2016 pooled analysis of data from 11 studies did not find a statistically significant benefit of IVIG therapy for mortality. 

Idiopathic Inflammatory Myopathies 
Idiopathic inflammatory myopathiesare a group of disorders characterized by inflammation of skeletal muscles and include dermatomyositis, polymyositis, and inclusion body myositis. Polymyositis and dermatomyositis involve weakness of the proximal muscles such as the muscles of the hips and thighs, upper arms, and neck. Dermatomyositis is associated with various characteristic skin manifestations. In inclusion body myositis, the muscles most affected are those of the wrists and fingers and the front of the thigh. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with dermatomyositis or polymyositis or inclusion body myositis. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review.

Patients 
The relevant populations of interest are individuals with dermatomyositis, polymyositis, or inclusion body myositis.

Interventions 
The therapy being considered is IVIG therapy. Patients with dermatomyositis, polymyositis, or inclusion body myositis are actively managed by neurologists, nephrologists and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat dermatomyositis, polymyositis, or inclusion body myositis: standard of care. 

Outcomes
The general outcomes of interest area change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. 

Follow-up at 39 months is of interest for dermatomyositis and polymyositis to monitor outcomes. Follow-up at 6, 12, and 24 months is of interest for inclusion body myositisto monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Dermatomyositis and Polymyositis 
Systematic Reviews 
Wang et al. (2012) published a systematic review on IVIG treatment for adults with refractory dermatomyositis or polymyositis.⁸⁵ Reviewers identified 14 studies including 2 RCTs, 9 prospective case series, and 3 retrospective case series. Eleven of 14 studies included patients with refractory disease. For example, a trial by Dalakas et al. (1993) compared prednisone plus IVIG with prednisone plus placebo in 15 patients with refractory dermatomyositis.⁸⁶ At 3 months, there were significant increases in muscle strength in the IVIG group, as measured by mean scores on the modified Medical Research Council scale (84.6 IVIG vs 78.6 placebo) and the Neuromuscular Symptom Scale (51.4 IVIG vs 45.7 placebo). Repeated transfusions every six to eight weeks can be required to maintain a benefit. 

Randomized Controlled Trials 
Miyasaka et al. (2012) in Japan conducted an RCT of 26 patients with corticosteroid-resistant polymyositis or dermatomyositis who had received high-dose corticosteroid therapy for at least 1 month.⁸⁷ Patients were randomized to IVIG (n = 12) or placebo (n = 14) once daily for 6 consecutive days. The primary endpoint was change from baseline mean manual muscle test scores at eight weeks. Change in mean manual muscle test was 11.8 points in the IVIG group and 9.9 points in the placebo group. This 1.9-point difference was not statistically significant (95% CI, -4.8 to 8.5). Other outcomes also did not differ significantly between groups.

Case Series 
A case series by Cherin et al. (2002) assessed 35 patients with polymyositis, all of whom had disease that required ongoing glucocorticoid therapy and none could be weaned from glucocorticoids despite trials of 1 or more additional therapies, showed some clinical benefit; 33 patients with initially elevated serum creatine kinase levels showed biochemical improvement; 25 of 35 showed improvement in muscle strength, which returned to near-normal in 10 of the 25 responders; 8 of 11 patients with esophageal dysfunction showed resolution of dysphagia; 12 of the 25 responders had complete clinical responses (absence of myositis activity) while receiving not more than prednisone 6 mg/d.⁸⁸ Mean follow-up for these patients was 39 months. Five patients discontinued all other medical treatments for myositis. 

Section Summary: Dermatomyositis and Polymyositis 
The evidence for IVIG treatment of dermatomyositis and polymyositis consists of multiple RCTs and noncomparative studies. A systematic review of 12 studies concluded that IVIG therapy is effective for adults with refractory polymyositis or dermatomyositis. However, a recent RCT failed to show significant differences in muscle test scores between IVIG and placebo. 

Inclusion Body Myositis 
Randomized Controlled Trials 
Dalakas et al. (1997) reported on a double-blind, placebo-controlled crossover study that compared IVIG with placebo in 19 patients with inclusion body myositis.⁸⁹ There was no statistically significant improvement in overall muscle strength in the IVIG group compared with the control (placebo) group. Two more recent RCTs published in 2000 and 2001 (58 IVIG patients) also found no significant functional improvement when IVIG treatment was compared with placebo.^90,91 

Section Summary: Inclusion Body Myositis 
Three RCTs of IVIG therapy for inclusion body myositis failed to show any improvements in overall muscle strength or functional status compared with placebo. 

Systemic Lupus Erythematosus
SLE is a chronic inflammatory disease that has protean manifestations and follows a relapsing and remitting course. It is characterized by an autoantibody response to nuclear and cytoplasmic antigens. SLE can affect any organ system, but it mainly attacks the skin, joints, kidneys, blood cells, and nervous system.

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with SLE. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with SLE. 

Interventions
The therapy being considered is IVIG therapy. IVIG therapy is proposed for SLE because of its immunomodulatory properties and because it prevents infection in patients taking immunosuppressive drugs. Patients with SLE are actively managed by rheumatologists, cardiologists, pulmonologists, nephrologists, and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat SLE: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
A systematic review by Sakthiswary et al. (2014) identified 13 studies on IVIG for the treatment of SLE.⁹² Three studies had control groups, and only one was an RCT.⁹³ Most studies were small; only 3 had more than 50 patients, and the single RCT included only 14 patients. In a meta-analysis of 6 studies (n = 216 patients), there was a statistically significant difference in SLE disease activity in IVIG-treated groups (standardized mean difference = 0.58; 95% CI, 0.22 to 0.95). This analysis was limited because there were few data in non-IVIG-treated patients. A meta-analysis of data from 8 studies on the effect of IVIG on complement levels found a pooled response rate of 30.9% (95% CI, 22.1% to 41.3%). Findings on other outcomes were not pooled.

There has been limited anecdotal experience and concerns about potential prothromboembolic effects and possible IVIG-associated azotemia in SLE.⁹⁴

Section Summary: SLE 
The evidence for IVIG treatment of SLE consists of a single RCT and multiple noncomparative studies. In a meta-analysis (six studies), IVIG treatment was associated with reduced disease activity. However, most studies included in the meta-analysis were observational, and good quality RCTs are lacking. Therefore, results were limited by methodologic limitations and the effect of IVIG therapy on health outcomes remain to be established.

Immune Optic Neuritis 
Optic neuritis is an inflammatory demyelinating condition that causes acute, usually monocular, visual loss. It is associated with multiple sclerosis, occurring in 50% of individuals at some time during the course of their illness. 

Clinical Context and Test Purpose 

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with immune optic neuritis. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with immune optic neuritis. 

Interventions 
The therapy being considered is IVIG therapy. Patients with immune optic neuritis are actively managed by ophthalmologists and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat immune optic neuritis: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at six months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication.

Randomized Controlled Trials 
Two RCTs have evaluated the potential benefit of IVIG for immune optic neuritis. Roed et al. (2005) randomized 68 in the acute phase of optic neuritis to IVIG (n = 34) or placebo (n = 34).⁹⁵ They found no differences in the visual outcome measure or disease activity as measured by magnetic resonance imaging after six months. 

Noseworthy et al. (2001) planned to randomize 60 patients with persistent acuity loss after optic neuritis to IVIG or placebo.⁹⁶ The trial was terminated early after 55 patients were enrolled because investigators did not find a difference in the logMAR visual scores at 6 months (p = 0.766). 

Section Summary: Immune Optic Neuritis 
The evidence for IVIG treatment of immune optic neuritis consists of two RCTs, both of which failed to demonstrate any benefit in visual outcome measures with IVIG. 

Crohn Disease 
Crohn disease is an inflammatory condition of unknown etiology that can affect any portion of the gastrointestinal tract, from the mouth to the perianal area, with a wide spectrum of clinical presentations. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Crohn disease.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review.

Patients 
The relevant population of interest are individuals with Crohn disease. 

Interventions 
The therapy being considered is IVIG therapy. Patients with Crohn disease are actively managed by gastroenterologists and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat Crohn disease: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
A systematic review by Rogosnitzky et al. (2012) of IVIG therapy for Crohn disease did not identify any randomized or nonrandomized controlled trials.⁹⁷ Reviewers found five case reports of IVIG used for single patients with Crohn disease, and the remaining literature identified included conference papers, abstracts only, or a nonsystematic review. 

Section Summary: Crohn Disease 
The evidence for IVIG treatment of Crohn disease consists of multiple case reports, which is not sufficiently robust to determine the efficacy of IVIG for this population.

Hemophagocytic Lymphohistiocytosis 
Hemophagocytic lymphohistiocytosis is an uncommon but potentially fatal syndrome of excessive immune activation resulting from overactive histiocytes and lymphocytes. It may be inherited or acquired. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with hemophagocytic lymphohistiocytosis. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with hemophagocytic lymphohistiocytosis. 

Interventions 
The therapy being considered is IVIG therapy. Patients with hemophagocytic lymphohistiocytosis are actively managed by immunologists and hematologists in an outpatient setting. 

Comparators 
The following therapies are currently being used to treat hemophagocytic lymphohistiocytosis: supportive care alone, chemotherapy, and allogeneic cell transplantation. 

Outcomes 
The general outcomes of interest are OS, DSS, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
A systematic review by Rajagopala et al. (2012) on diagnosing and treating hemophagocytic lymphohistiocytosis in the tropics identified 156 cases; a portion of these patients were treated with IVIG.⁹⁸ Steroids were the most common treatment. IVIG was used in 30% of children and in 4% of adults. Hemophagocytic syndrome-related mortality occurred in 32% of children and in 28% of adults. 

Case Series 
Published literature on the use of IVIG in hemophagocytic syndrome is limited to small case series.^99,100,101 

Section Summary: Hemophagocytic Lymphohistiocytosis 
The evidence for IVIG treatment of hemophagocytic lymphohistiocytosis consists of multiple case series and reports, which is not sufficiently robust to determine the efficacy of IVIG for this population. 

Warm Antibody Autoimmune Hemolytic Anemia 
Also known as autoimmune hemolytic anemia, warm antibody autoimmune hemolytic anemia occurs commonly due to IgG antibodies that react with protein antigens on the red blood cell surface at body temperature. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with warm antibody hemolytic anemia, refractory to prednisone and splenectomy.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with warm antibody hemolytic anemia, refractory to prednisone and splenectomy. 

Interventions 
The therapy being considered is IVIG therapy. Patients with warm antibody hemolytic anemia, refractory to prednisone and splenectomy, are actively managed by hematologists and primary care providers in an outpatient setting.

Comparators
The following therapies are currently being used to treat warm antibody hemolytic anemia: prednisone, splenectomy, and cytotoxic medications. 

Outcomes 
The general outcomes of interest are a change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at three weeks is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Nonrandomized Studies 
Published literature on the use of IVIG in warm antibody autoimmune hemolytic anemia is limited to observational data for 37 patients pooled from 3 institutions¹⁰² and a case report.¹⁰³ Overall, 29 (39.7%) of 73 patients responded to IVIG therapy. Because of limited therapeutic value, it is used in patients refractory to conventional therapy with prednisone and splenectomy or as a conjunctive therapy in patients with very severe disease. Further, the effect is usually transient, unless repeated courses are given every three weeks. 

Section Summary: Warm Antibody Autoimmune Hemolytic Anemia
The evidence for IVIG treatment of warm antibody autoimmune hemolytic anemia consists of pooled case series and a single case report, which is not sufficiently robust to determine the efficacy of IVIG for this population. 

Antiphospholipid Syndrome 
Antiphospholipid syndrome is an autoimmune disease that results from the development of an antibody against phospholipid proteins, which causes venous or arterial thromboses and/or pregnancy morbidity. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with antiphospholipid syndrome. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with antiphospholipid syndrome. 

Interventions 
The therapy being considered is IVIG therapy. Patients with antiphospholipid syndrome are actively managed by hematologists, rheumatologists, and primary care providers in an outpatient setting. 

Comparators 
The following therapies are currently being used to treat antiphospholipid syndrome: anticoagulant therapy and antiplatelet therapy. 

Outcomes 
The general outcomes of interest are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Case Reports 
Published literature on the use of IVIG in antiphospholipid syndrome includes a pooled analysis of 250 single case reports from a registry.¹⁰⁴ Results showed that a higher proportion of patients survived after the episode of antiphospholipid syndrome if they received triple therapy with anticoagulants, corticosteroids, plasma exchange, and/or IVIGs compared with combinations that did not use plasma exchange, IVIG, or both. 

Section Summary: Antiphospholipid Syndrome 
The evidence for IVIG treatment of antiphospholipid syndrome consists of pooled case series from a registry, which is not sufficiently robust to determine the efficacy of IVIG for this population. 

Alloimmune Processes 
Neonatal Alloimmune Thrombocytopenia 
Fetal and neonatal thrombocytopenia occurs when a maternal antibody directed against a paternal platelet-antigen crosses the placenta and causes thrombocytopenia in the fetus. Intracranial hemorrhage (ICH) occurs in 10% to 30% of affected neonates. Currently, screening for this condition is unavailable and, thus, thrombocytopenia is only identified at birth. However, subsequent fetuses that are platelet-antigen positive also will be at risk for thrombocytopenia, and the severity of thrombocytopenia may be increased. The treatment has focused on neonatal platelet transfusions, corticosteroids, and IVIG. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with neonatal alloimmune thrombocytopenia. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are neonates with alloimmune thrombocytopenia. 

Interventions 
The therapy being considered is IVIG therapy. Neonates with alloimmune thrombocytopenia are actively managed by pediatricians and primary care providers in an outpatient setting. 

Comparators 
The following practices are currently being used to treat neonatal alloimmune thrombocytopenia: platelet transfusion and supportive care alone. 

Outcomes 
The general outcomes of interest are DSS, change in disease status, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
Rayment et al. (2011), in a Cochrane review, summarized the results of 4 RCTs on the maternal administration of corticosteroids and IVIG in pregnancies with neonatal alloimmune thrombocytopenia in 206 women.¹⁰⁵ Reviewers concluded that the optimal management of fetomaternal alloimmune thrombocytopenia remains unclear. Lack of complete data sets for two trials and differences in interventions precluded the pooling of data from these trials. 

Randomized Controlled Trials 
Paridaans et al. (2015) evaluated the effectiveness of a lower dose of IVIG (0.5 g/kg/wk vs 1 g/kg/wk) in an RCT of 23 women.¹⁰⁶ The primary outcome was fetal or neonatal ICH. The median newborn platelet count was 81×10⁹/L in the 0.5-g/kg group and 110×10⁹/L in the 1-g/kg group (p = 0.644). 

Berkowitz et al. (2007) showed good outcomes and comparable results between the IVIG group and the IVIG plus prednisone group in standard-risk pregnancies.¹⁰⁷ In another trial, Berkowitz et al. (2006) did not demonstrate a difference in standard-risk pregnancies but did demonstrate that IVIG and prednisone were more effective in raising the fetal platelet count in high-risk pregnancies.¹⁰⁸ 

Bussel et al. (1996) did not find any differences in the fetal platelet counts between IVIG and IVIG with steroids.¹⁰⁹ Although there was no placebo-controlled arm, results can be compared with the course in a prior affected sibling, because the natural history of the disease suggests that subsequent births should be similar, if not more severely, affected with thrombocytopenia. The trial reported a mean increase in platelet count of 69,000/mL. There were no instances of ICHs, although hemorrhage had occurred previously in ten untreated siblings. 

There are no RCTs evaluating the efficacy of IVIG or steroids alone vs placebo in alloimmune thrombocytopenia. Trials of this nature would be unethical because of the known risk of ICH with this condition. 

Section Summary: Neonatal Alloimmune Thrombocytopenia 
The evidence for IVIG treatment of neonatal alloimmune thrombocytopenia consists of multiple RCTs summarized in a Cochrane review; the review showed that optimal management with IVIG with or without corticosteroids remains unclear. IVIG has been shown to increase platelet counts in standard-risk pregnancies in individual studies. 

Recurrent Spontaneous Abortion 
Recurrent spontaneous abortion is defined as 3 or more pregnancies resulting in spontaneous abortion before 16 to 20 weeks of gestational age. Women with recurrent spontaneous abortion frequently have immunologic abnormalities, particularly antiphospholipid antibodies whose incidence may increase with each subsequent pregnancy loss. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in women with recurrent spontaneous abortion. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are women with recurrent spontaneous abortion. 

Interventions 
The therapy being considered is IVIG therapy. Women with recurrent spontaneous abortion are actively managed by obstetricians-gynecologists in an outpatient setting. 

Comparators 
The following practice is currently being used to treat recurrent spontaneous abortion: supportive care. 

Outcomes 
The general outcomes of interest are DSS, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Systematic Reviews 
A Cochrane review by Porter et al. (2006) assessed various immunotherapies for treating recurrent miscarriage and concluded that IVIG therapy provides no significant beneficial effect over placebo in preventing further miscarriages.¹¹⁰ Meta-analyses published in 2015 and 2016 that included 11 RCTs also found no significant difference in the number of live births with IVIG vs placebo or treatment as usual.^111,112 

Randomized Controlled Trials 
An RCT by Christiansen et al. (2002) evaluated 58 women with at least 4 unexplained miscarriages and compared IVIG with placebo.¹¹³ Using the intention to treat analysis, the live birth rate was similar for both groups; also, there were no differences in neonatal data (e.g., birth weight, gestational age at delivery). 

Likewise, a multicenter RCT by Branch et al. (2000) compared heparin plus low-dose aspirin with or without IVIG in women with a lupus anticoagulant, anticardiolipin antibody, or both, and found no significant differences.¹¹⁴ 

A blinded RCT by Jablonowska et al. (1999) assessed 41 women treated with IVIG or saline placebo also found no differences in live birth rates.¹¹⁵ 

Section Summary: Recurrent Spontaneous Abortion 
The evidence for IVIG treatment of recurrent spontaneous abortion consists of multiple RCTs summarized in a Cochrane review; it concluded that IVIG therapy provides no significant beneficial effect over placebo in preventing further miscarriages. 

Miscellaneous Indications 
Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections 

PANDAS is a term used to describe a subset of children whose symptoms of obsessive-compulsive disorder (or tic disorders) are exacerbated by group A streptococcal infection. This syndrome is not well-understood, and the diagnosis of PANDAS requires expert consultation. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in children with PANDAS. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are children with PANDAS. 

Interventions 
The therapy being considered is IVIG therapy. Children with PANDAS are actively managed by pediatricians and neurologists in an outpatient setting. 

Comparators 
The following practice is currently being used to treat PANDAS: antibiotic therapy alone. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, and treatment-related mortality and morbidity. Follow-up at one month is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Randomized Controlled Trials 
Williams et al. (2016) randomized 35 children who met diagnostic criteria for PANDAS and had moderate-to-severe obsessive-compulsive disorder symptoms to treatment with 2 treatment sessions of IVIG or placebo.¹¹⁶ After a six-week double-blind treatment phase, nonresponders could continue treatment on an open-label basis. The primary outcome at six weeks, the Children’s Yale-Brown Obsessive Compulsive Scale total score, did not differ significantly between groups. There was a mean decrease in the Children’s Yale-Brown Obsessive Compulsive Scale of 23.9% in the IVIG group and 11.7% in the placebo group (effect size, 0.28; 95% CI, -0.39 to 0.95). Improvements in other outcomes (e.g., mean Clinical Global Impressions improvement scores) also did not differ significantly between groups. A total of 24 participants met the criteria for nonresponse at 6 weeks and received open-label IVIG. At week 12, scores on the Children’s Yale-Brown Obsessive Compulsive Scale improved significantly compared with 6 weeks; however, the 12-week analysis did not include a placebo comparison. 

An RCT by Perlmutter et al. (1999) included 30 children who had new or severe exacerbations of obsessive-compulsive disorder or tic disorder after streptococcal infections.¹¹⁷ Patients were randomized to IVIG, plasma exchange, or placebo (ten per group). At the one-month follow-up, IVIG and plasma exchange showed statistically significant improvements in obsessive-compulsive symptoms, anxiety, and overall functioning. The trial included only 10 children who were treated with IVIG. 

Section Summary: PANDAS 
Two placebo-controlled randomized trials have evaluated IVIG for PANDAS. A 2016 trial with 35 children did not find significant benefits with IVIG compared with placebo at the end of the 6-week double-blind phase. The other trial found significant benefits of IVIG over placebo at one month but included only ten children with PANDAS. Due to the mixed findings of the RCTs, the small sample sizes and the short duration of double-blind interventions, the evidence is insufficient to draw conclusions about the impact of IVIG on health outcomes in children with PANDAS. 

Autism Spectrum Disorder 
Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in social communication and social interaction and restricted repetitive patterns of behavior, interests, and activities. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with an autism spectrum disorder. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with an autism spectrum disorder. 

Interventions 
The therapy being considered is IVIG therapy. Patients with autism spectrum disorder are actively managed by primary care providers, pediatricians, occupational therapists, clinical psychologists, and neurologists in an outpatient setting. 

Comparators 
The following practice is currently being used to treat autism spectrum disorder: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at six months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Case Series 
The evidence base supporting the use of IVIG in autism includes case series. One included 10 patients with abnormal immune parameters who received IVIG therapy monthly.¹¹⁸ After six months, five of ten patients showed marked improvement in several autistic characteristics. Another two case series failed to replicate these findings. In the second, one of ten patients showed improvements in autistic symptoms after receiving IVIG.¹¹⁹ No improvements were observed in the third series.¹²⁰ 

No randomized comparative trials evaluating IVIG therapy in autism were identified. 

Section Summary: Autism Spectrum Disorder 
The evidence for IVIG treatment of autism spectrum disorder consists of multiple case series with conflicting findings; one case series reported benefit while two others failed to replicate those findings. 

Complex Regional Pain Syndrome 
CRPS is defined as a disorder of the extremities characterized by regional pain that is disproportionate in time or degree to the usual course of any known trauma or other lesions. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with CRPS. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with CRPS. 

Interventions 
The therapy being considered is IVIG therapy. Patients with CRPS are actively managed by physiatrists, occupational therapists, physical therapists, and neurologists in an outpatient setting. 

Comparators 
The following practice is currently being used to treat CRPS: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, morbid events, QOL, and treatment-related mortality and morbidity. Follow-up at 14 days is of interest to monitor outcomes 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Randomized Controlled Trials 
Goebel et al. (2017) conducted a 1:1 parallel, randomized, placebo-controlled, multicenter trial to confirm the efficacy of low-dose IVIG compared with placebo in reducing pain in adults who had CRPS of 1 to 5 years in duration.¹²¹ IVIG 0.5 g/kg of body weight or saline placebo on days 1 and 22 were administered after 111 patients were randomized. An 11-point (0- to 10-point) rating scale was used to measure the primary outcome of 24-hour average pain intensity. Mean pain scores were 6.9 points for placebo and 7.2 points for IVIG at six weeks demonstrating that low-dose immunoglobulin treatment was not effective in relieving pain in moderate-to-severe CRPS patients. 

Goebel et al. (2010) reported on the use of IVIG treatment for CRPS in a crossover double-blinded RCT conducted at an academic pain management center in the U.K.¹²² The trial randomized 13 patients refractory to standard treatment to IVIG or normal saline. Median daily pain intensity score for each 14-day period was 6.21 after IVIG infusion vs 7.35 after saline infusion, a difference of 1.14 points. Trialists reported that the mean pain intensity was 1.55 points lower after IVIG than after saline (95% CI, 1.29 to 1.82; p < 0.001). 

Section Summary: CRPS 
The evidence for IVIG treatment of CRPS consists of a small crossover RCT that showed reductions in pain scores compared with placebo. However, the evidence is insufficient to draw conclusions about the impact of IVIG on health outcomes in those who suffer from CRPS. 

Alzheimer Disease 
Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with AD. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with AD. 

Interventions 
The therapy being considered is IVIG therapy. Patients with AD are actively managed by geriatricians, neurologists and primary care providers in an outpatient setting.

Comparators 
The following practice is currently being used to treat AD: standard of care. 

Outcomes 
The general outcomes of interest are OS,DSS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 12 or 24 months is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Randomized Controlled Trials 
Three placebo-controlled double-blind, randomized trials in patients with AD were identified. Two included patients with mild-to-moderate AD. Relkin et al. (2017) reported on 390 patients treated with 1 of 2 doses of IVIG (0.2 or 0.4 g/kg every 2 weeks for 18 months) or placebo.¹²³ The primary outcomes were a change from baseline to 18 months on the cognitive subscale of the Alzheimer Disease Assessment scale and on the Alzheimer Disease Cooperative Study-Activities of Daily Living Inventory. Neither outcome was significantly improved in either IVIG groups compared with the placebo group. 

Kile et al. (2017) assessed 50 patients with mild cognitive impairment (MCI) related to AD.¹²⁴ Patients were stratified into early and late MCI stages based on scores on the Clinical Dementia Rating, Sum of Boxes test (≤ 1 for the early MCI group and >1 for the late MCI group). Patients received a total IVIG dose of 2g/kg over five sessions, or placebo. The primary outcome was brain atrophy, defined as annualized percent change in the ventricular volume measured by magnetic resonance imaging. In unadjusted analyses, annualized percent change in the ventricular volume did not differ significantly between groups at 12 or 24 months. In a subgroup analysis, the annualized percent change in the ventricular volume was significantly lower in the IVIG compared with the placebo group in patients with early MCI but not late MCI at 12 months, and there was no significant difference at 12 months in either the early or late MCI groups. Secondary outcomes, cognition scores, and conversion to AD dementia did not differ between the IVIG and placebo groups at 12 or 24 months. As with the primary outcome, for several secondary outcomes, IVIG showed a significant benefit in the early MCI group at 12 months but not 24 months. 

In a trial by Dodel et al. (2013) with 56 patients, the primary outcome (area under the curve of plasma amyloid β 1-40) did not differ between the IVIG and the placebo groups.¹²⁵ Secondary outcomes, including cognitive and functional scales, also did not differ between groups. 

Section Summary: AD 
Three double-blind placebo-controlled randomized trials have evaluated IVIG in patients with AD. With the exception of a few subgroup analyses by MCI status, IVIG did not show significantly better outcomes than placebo for brain atrophy, level of plasma amyloid β 1-40, or cognition and function. Studies differed in factors such as treatment protocols, outcomes assessed, and two of the three3 had relatively small sample sizes. Additional RCTs could be conducted to confirm whether IVIG benefits patients with early MCI. 

Paraproteinemic Neuropathy 
Paraproteinemic neuropathy is a heterogeneous set of neuropathies characterized by the presence of paraproteins, which are immunoglobulins produced in excess by an abnormal clonal proliferation of B lymphocytes or plasma cells. Paraproteinemic neuropathy may be caused by the interaction of antibodies with specific antigenic targets on peripheral nerves or by deposition of immunoglobulins or amyloid. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with paraproteinemic neuropathy. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with paraproteinemic neuropathy. 

Interventions 

The therapy being considered is IVIG therapy. Patients with paraproteinemic neuropathy are actively managed by primary care providers and neurologists in an outpatient setting. 

Comparators 
The following practice is currently being used to treat paraproteinemic neuropathy: standard of care. 

Outcomes 
The general outcomes of interest area change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at two weeks is of interest to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Randomized Controlled Trials 
An RCT by Comi et al. (2002) focused on short-term outcomes at 2 weeks in 22 patients.¹²⁶ No significant differences were found between the treatment and placebo groups. 

Results of a double-blind, placebo-controlled, randomized crossover trial by Dalakas et al. (1996) compared IVIG with placebo in 11 patients with paraproteinemic IgM demyelinating polyneuropathy showed only a mild and transitory effect in 3 patients.¹²⁷ 

Section Summary: Paraproteinemic Neuropathy 
The evidence for IVIG treatment of paraproteinemic neuropathy consists of two RCTs with conflicting findings; the first reported a small benefit while the larger failed to replicate those findings. 

Chronic Fatigue Syndrome 
Chronic fatigue syndrome (also called systemic exertion intolerance disease) is a complex and controversial disease with multiple definitions. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with chronic fatigue syndrome. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with chronic fatigue syndrome. 

Interventions 
The therapy being considered is IVIG therapy. Patients with chronic fatigue syndrome are actively managed by rheumatologists and primary care providers in an outpatient setting. 

Comparators 
The following practice is currently being used to treat chronic fatigue syndrome: standard of care. 

Outcomes 
The general outcomes of interest are symptoms, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is to monitor outcomes. 

Study Selection Criteria 
Methodologically credible studies were selected as stated in the initial indication. 

Randomized Controlled Trials 
Numerous noncomparative studies have shown subjective benefits of IVIG therapy on chronic fatigue syndrome, but a double-blind, randomized, placebo-controlled trial by Vollmer-Conna et al. (1997) in 99 patients with chronic fatigue syndrome reported no therapeutic benefit of IVIG.¹²⁸ 

Section Summary: Chronic Fatigue Syndrome 
The evidence for IVIG treatment of chronic fatigue syndrome consists of noncomparative studies and an RCT that failed to show a benefit of IVIG. 

Acute Myocarditis 
Acute myocarditis is a sudden inflammation of myocardium that can occur in individuals of all ages. It is presumed to start as a viral infection, although autoimmune and idiopathic forms also occur. It remains unclear whether the primary problem is the most commonly ongoing damage from the virus, a post-infectious inflammatory reaction, or a combination of the two. 

Clinical Context and Test Purpose 
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with acute myocarditis. 

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions? 

The following PICOs were used to select literature to inform this review. 

Patients 
The relevant population of interest are individuals with acute myocarditis. 

Interventions 
The therapy being considered is IVIG therapy. Patients with acute myocarditis are actively managed by cardiologists in an inpatient setting. 

Comparators 
The following therapy is currently being used to treat acute myocarditis: heart failure therapy alone. 

Outcomes 
The general outcomes of interest are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Systematic Reviews
The literature has been summarized in a Cochrane review by Robinson et al. (2015)¹²⁹ that included a 2001 placebo-controlled randomized trial of 62 adults with recent-onset dilated cardiomyopathy¹³⁰ and a 2012 quasi-randomized study of 83 children with suspected viral encephalitis and associated myocarditis with a left ventricular ejection fraction less than 0.40.¹³¹ Both trials were rated as very low quality and had a high-risk of bias. In the RCT of adults, event-free survival did not differ significantly but favored the control group (OR = 0.52; 95% CI, 0.12 to 2.30). The major limitation was that some patients did not have viral myocarditis (only 10 of 62 patients showed inflammation on cardiac biopsy). In the quasi-randomized trial in children, the incidence of event-free survival was 25 (96%) of 26 in the treated group and 44 (77%) of 57 in the control group (OR = 7.39; 95% CI, 0.91 to 59.86).

Huang et al. (2019) published a meta-analysis assessing IVIG for patients with acute myocarditis.¹³² Thirteen studies (1534 participants), published between 1994 and 2017, were included. In-hospital mortality rates (pooled results: OR 0.44, 95% CI 0.17-0.71, p < 0.001) were significantly reduced for the IVIG group compared with patients who did not receive IVIG, and left ventricular ejection fraction (OR 1.73, 95% CI 1.34 to 2.13, p < 0.001) was significantly increased for IVIG. The study was limited by the IVIG doses not being uniformly predefined and by the limited follow-up durations (mainly between 6 and 12 months) across the included studies.

Retrospective Studies
Heidendael et al. (2017) reported on 94 children with new-onset dilated cardiomyopathy in a retrospective cohort study with a median follow-up of 33 months.¹³³ After viral tests were performed, 18 (19%) children met diagnostic criteria for “probably or definite viral myocarditis,” and IVIG was administered to 21 (22%) patients. Treatment was associated with a higher recovery rate within 5 years, compared with nontreated children (70 vs 43%; p = 0.045), however, the hazard ratio for recovery with IVIG was not significant (hazard ratio = 2.1; 95% CI, 1.0 to 4.6; p = 0.056) after correction for possible cofounders. The authors concluded that IVIG treatment was associated with better improvement of systolic left ventricular function and better recovery, but did not influence transplant-free survival.

Multiple case reports have suggested that patients with acute myocarditis may benefit from high-dose IVIG.⁹⁴ Spontaneous rapid or gradual improvement is common with acute myocarditis, and improvement noted in these case series might have been part of the natural history of the disease.

Section Summary: Acute Myocarditis
The evidence for IVIG treatment of dilated cardiomyopathy syndrome consists of multiple noncomparative studies, a quasi-randomized trial, and an RCT. All studies had a high-risk of bias. High-quality RCTs are needed to demonstrate the benefit of IVIG for viral myocarditis.

Refractory Recurrent Pericarditis
Refractory recurrent pericarditis is defined as recurrent pericarditis not responding to conventional anti-inflammatories such as aspirin, nonsteroidal inflammatory drugs, corticosteroids, and colchicine.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with refractory recurrent pericarditis.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals with refractory recurrent pericarditis.

Interventions
The therapy being considered is IVIG therapy. Patients with refractory recurrent pericarditis are actively managed by cardiologists in an outpatient setting.

Comparators
The following therapy is currently being used to treat refractory recurrent pericarditis: heart failure therapy alone.

Outcomes
The general outcomes of interest are OS, change in disease status, QOL, and treatment-related mortality and morbidity. A follow-up to 36 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Systematic Reviews
Imazio et al. (2016) conducted a systematic review and summarized data of 30 patients (4 case series, 13 case reports).¹³⁴ Approximately 47% of patients had idiopathic recurrent pericarditis, 10% had an infective cause, and the remainder had asystemic inflammatory disease. IVIG was generally administered at a dose of 400 to 500 mg/kg/d for 5 consecutive days, with repeated cycles according to the clinical response. Overall, recurrences occurred in 26.6% of cases after the first IVIG cycle, and 22 (73.3%) of the 30 patients were recurrence-free after a mean follow-up of approximately 33 months.

Section Summary: Refractory Recurrent Pericarditis
The evidence for IVIG treatment of refractory recurrent pericarditis consists of multiple case reports and case series that reported benefit. Controlled trials are lacking.

Stiff-Person Syndrome
Stiff-person syndrome is a rare acquired neurologic disorder characterized by progressive muscle stiffness, rigidity, and spasm involving the axial muscles, resulting in severely impaired ambulation. It is caused by increased muscle activity due to decreased inhibition of the central nervous system. If left untreated, stiff person syndrome can progress to cause difficulty walking and significantly impact a person's ability to perform routine, daily tasks.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with stiff-person syndrome.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals with stiff-person syndrome.

Interventions
The therapy being considered is IVIG therapy. Patients with the stiff-person syndrome are actively managed by primary care providers, neurologists and physical therapists in an outpatient setting.

Comparators
The following therapies are currently being used to treat stiff-person syndrome: benzodiazepines and baclofen.

Outcomes
The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at 24 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Case Reports
Multiple case reports have suggested that patients with the stiff-person syndrome may benefit from IVIG. The benefit was confirmed in a small crossover study by Dalakas et al. (2001), which compared IVIG with placebo in 16 patients who had the stiff-person syndrome and anti-GAD65 autoantibodies who were maintained on current doses of benzodiazepines throughout the study.¹³⁵ After a one-month washout period, patients were crossed over to three months of the alternative treatment. Stiffness scores decreased significantly on IVIG, but not on placebo, regardless of order. Eleven (69%) patients were able to walk more easily or without assistance; the frequency of falls decreased, and patients were able to perform work-related or household tasks. The duration of benefit lasted six weeks to one year without additional treatment.

Section Summary: Stiff-Person Syndrome
The evidence for IVIG treatment of stiff person syndrome consists of an RCT and multiple noncomparative studies that confirmed the benefit of IVIG in terms of reductions in stiffness as well as improvements in mobility and function.

Noninfectious Uveitis
Noninfectious uveitis is the inflammation of the eye that results from eye trauma, anomalous immune processes, or unknown etiology.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with noninfectious uveitis.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals with noninfectious uveitis.

Interventions
The therapy being considered is IVIG therapy. Patients with noninfectious uveitis are actively managed by ophthalmologists in an outpatient setting.

Comparators
The following therapies are currently being used to treat noninfectious uveitis: topical glucocorticoids, difluprednate, intraocular glucocorticoids, systemic glucocorticoids, and systemic immunomodulating agents.

Outcomes
The general outcomes of interest are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12 and 24 months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Case Series
Two small case series of 18 and 10 patients, respectively, have reported measurable improvements in visual acuity after IVIG therapy.^136,137 Collectively, these two studies represent insufficient evidence to draw conclusions about efficacy.

Section Summary: Noninfectious Uveitis
The evidence for IVIG treatment of noninfectious uveitis consists of two small case series that have reported measurable improvements in visual acuity after IVIG therapy. However, the evidence is insufficient to draw conclusions about the impact of IVIG on health outcomes in those who suffer from noninfectious uveitis.

Postpolio Syndrome
Although polio no longer poses a major public health threat in the U.S., many patients live with the sequelae of paralytic polio. Many polio survivors experience a modest decline in function and muscle strength over many years that may reflect the natural history of polio.

Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with postpolio syndrome.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals with postpolio syndrome.

Interventions
The therapy being considered is IVIG therapy. Patients with the postpolio syndrome are actively managed by primary care providers, neurologists and physical therapists in an outpatient setting.

Comparators
The following practice is currently being used to treat postpolio syndrome: supportive care alone.

Outcomes
The general outcomes of interest are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. Follow-up at three months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Systematic Reviews
Huang et al. (2015) published a systematic review and meta-analysis of RCTs and nonrandomized prospective studies on IVIG treatment of the postpolio syndrome.¹³⁸ Reviewers identified 3 RCTs (n = 241 patients) and 5 prospective studies (n = 267 patients). The primary outcomes of interest were the severity of pain, fatigue, and change in muscle strength two to three months after IVIG administration. Meta-analyses of RCT data found no statistically significant differences between IVIG- and placebo-treated groups for any of these outcomes. For example, the pooled MD in pain scores (0-to-10 visual analog scale) from the 3 RCTs was -1.02 (95% CI, -2.51 to 0.47). Meta-analysis of the 2 RCTs that reported a change in fatigue scores found a weighted MD of 0.28 (95% CI, -1.56 to 1.12). The small number of RCTs and the negative findings of this systematic review represent insufficient evidence of the efficacy of IVIG for the postpolio syndrome.

Section Summary: Postpolio Syndrome
The evidence for IVIG treatment of postpolio syndrome consists of multiple RCTs and noncomparative studies summarized in a systematic review; it concluded that IVIG treatment was not associated with a reduction in pain and fatigue or an improvement in muscle strength.

Necrotizing Fasciitis
Clinical Context and Test Purpose
The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with necrotizing fasciitis.

The question addressed in this evidence review is: Is IVIG therapy an effective treatment for various autoimmune and nonautoimmune conditions?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are individuals with necrotizing fasciitis.

Interventions
The therapy being considered is IVIG therapy. Patients with necrotizing fasciitis are actively managed by general surgeons, plastic surgeons, and infectious disease doctors in an inpatient setting.

Comparators
The following therapies and practices are currently being used to treat necrotizing fasciitis: antibiotics and surgical removal of tissue.

Outcomes
The general outcomes of interest are OS, symptoms, functional outcomes, and treatment-related mortality and morbidity. A follow-up at three months is of interest to monitor outcomes.

Study Selection Criteria
Methodologically credible studies were selected as stated in the initial indication.

Randomized Controlled Trials
Madsen et al. (2017) published a placebo-controlled randomized trial evaluating IVIG for patients with necrotizing soft tissue infection(e.g., necrotizing fasciitis).¹³⁹ The trial included 100 patients with confirmed necrotizing soft tissue infection who were admitted or had planned admissions to the intensive care unit. The primary outcome was patient-reported physical function at 6 months, assessed using the Physical Component Summary score of the 36-Item Short-Form Health Survey. The mean Physical Component Summary score adjusted for the site of infection was 36 in the IVIG group and 21 in the placebo group. The difference between groups was not statistically significant (p = 0.81). Other outcomes (i.e., mortality, use of life support in the intensive care unit, bleeding, amputation) did not differ significantly between groups.

Section Summary: Necrotizing Fasciitis
The evidence for IVIG treatment of necrotizing fasciitis consists of an RCT that did not find a significant difference in outcomes between IVIG and placebo. The evidence is insufficient to draw conclusions on the impact of IVIG on health outcomes in this population.

Summary of Evidence
Immunodeficiency States
For individuals who have primary humoral immunodeficiency who receive IVIG or SCIG therapy, the evidence includes multiple RCTs and noncomparative studies. The relevant outcomes are OS, symptoms, change in disease status, morbid events, functional outcomes, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG and SCIG therapy improved disease-related outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are undergoing HCT who receive IVIG therapy (prophylaxis), the evidence includes multiple RCTs, systematic reviews, and a meta-analysis. The relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG for routine prophylaxis of infection in patients undergoing HCT was not associated with survival benefit or reduction in infection. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who are at risk of acute ABMR after solid organ transplants who receive IVIG therapy, the evidence includes multiple RCTs, noncomparative observational studies, systematic reviews, and meta-analysis. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG for prophylaxis of infection in patients with high panel reactive antibody levels was not associated with a survival benefit or reduction in infection. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have acute ABMR after solid organ transplants who receive IVIG therapy, the evidence includes retrospective case series and a systematic review. The relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG treatment for ABMR has shown potential benefits in retrospective or small prospective studies. Larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Infections
For individuals who have CLL with recurrent bacterial infections associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for recurrent bacterial infections associated with hypogammaglobulinemia in CLL patients has shown reductions in minor and moderate infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are HIV-infected children with recurrent bacterial infection associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes a single RCT. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for the prevention of opportunistic infections in HIV-infected children has shown reductions in minor and serious infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are preterm and low birth weight infants and at risk for sepsis who receive IVIG therapy (prophylaxis), the evidence includes multiple RCTs and a systematic review. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for prophylaxis of neonatal sepsis has shown a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who are preterm and low birth weight infants with sepsis who receive IVIG therapy (treatment), the evidence includes multiple RCTs and a systematic review. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for neonatal sepsis did not differ significantly in the rates of death or major disability. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who are adults with sepsis who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. The relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for adult sepsis showed reductions in mortality in the meta-analysis. However, multiple factors preclude recommending the routine use of IVIG to treat sepsis. They include the preponderance of small low-quality studies, the use of heterogeneous dosing regimens, types of IVIG preparations used, and changes over time in the management of sepsis. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have severe anemia associated with human parvovirus B19 who receive IVIG therapy, the evidence includes case series. The relevant outcomes are a change in disease status, treatment-related mortality, and treatment-related morbidity. Although observed improvements in outcomes have suggested potential benefits with IVIG therapy, data are retrospective. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have toxic shock syndrome who receive IVIG therapy, the evidence includes a small RCT and multiple observational studies. The relevant outcomes are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for toxic shock syndrome in adult women has shown reductions in mortality in the small RCT and in multiple observational studies. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Autoimmune and Inflammatory Conditions
For individuals who have ITP who receive IVIG therapy, the evidence includes multiple RCTs, a systematic review, a meta-analysis, and noncomparative studies. The relevant outcomes are DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with corticosteroids, IVIG therapy improved platelet counts. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have GBS who receive IVIG therapy, the evidence includes multiple RCTs, a systematic review, and a meta-analysis. The relevant outcomes are OS, DSS, symptoms, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with plasma exchange or combination therapy with plasma exchange, IVIG therapy showed similar outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have Kawasaki disease who receive IVIG therapy, the evidence includes multiple RCTs, a systematic review, and a meta-analysis. The relevant outcomes are disease-specific mortality, change in disease status, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown significant decreases in new coronary artery abnormalities. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have granulomatosis with polyangiitis (Wegener granulomatosis) who receive IVIG therapy, the evidence includes systematic reviews and an RCT. The relevant outcomes are disease-specific mortality, change in disease status, and treatment-related mortality and morbidity. The success of IVIG in Kawasaki disease has led to the investigation of IVIG therapy for other vasculitides such as Wegener granulomatosis. A 2013 Cochrane review identified 1 RCT on IVIG for Wegener granulomatosis. This small trial found significantly more responders in the IVIG treatment group at three months-but no significant differences after three months, or in the frequency of relapse or use of other medications. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have CIDP who receive IVIG therapy, the evidence includes multiple RCTs, a systematic review, and a meta-analysis. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have CIDP who receive SCIG therapy, the evidence includes two RCTs. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Only one RCT has directly compared SCIG with IVIG in patients who had CIDP and conclusions about the relative efficacy of the treatments cannot be drawn due to methodologic limitations (eg, 45% of patients withdrew from the trial). The other RCT demonstrated that the use of SCIG for the maintenance of CIDP might be effective, with relatively low adverse events, but this trial also had a number of limitations (e.g., small sample, 30% dropout rate). The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have MMN who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. The relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have Eaton-Lambert myasthenic syndrome who receive IVIG therapy, the evidence includes an RCT and multiple observational studies. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful improvements in outcomes assessing muscle strength and activity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have NMO who receive IVIG therapy, the evidence includes multiple observational studies. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Studies have shown that IVIG treatment may benefit patients who are refractory to first-line treatment with steroids or plasma exchange, particularly children. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have severe refractory myasthenia gravis or myasthenic exacerbation who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. The relevant outcomes are OS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. Compared with plasma exchange, IVIG therapy did not show significantly improved outcomes but was better tolerated. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have RRMS who receive IVIG therapy, the evidence includes multiple RCTs and technology assessments. The relevant outcomes are OS, DSS, symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. According to technology assessments, IVIG therapy is no longer considered a treatment of choice for RRMS. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have autoimmune mucocutaneous blistering diseases who receive IVIG therapy, the evidence includes two RCTs, a systematic review, and multiple uncontrolled studies. The relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. A systematic review found improvements in over 90% of patients. RCTs have reported benefits in disease activity in the population as a whole (one trial) or subgroup of patients with severe disease (one trial). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have TEN or SJS who receive IVIG therapy, the evidence includes systematic reviews of observational studies. The relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. No RCTs have evaluated IVIG for TEN or SJS; most trials that have, have been uncontrolled. A 2016 pooled analysis of data from 11 studies did not find a statistically significant benefit of IVIG therapy for mortality. Compared with placebo, IVIG therapy has not shown statistically significant benefits for mortality. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have dermatomyositis or polymyositis who receive IVIG therapy, the evidence includes two RCTs, multiple noncomparative observational studies, and a systematic review. The relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. In one of the RCTs, compared with placebo, IVIG therapy showed improvements in muscle strength. A large case series also noted improvements in most patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have inclusion body myositis who receive IVIG therapy, the evidence includes multiple RCTs. The relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy failed to show improvements in muscle strength. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have SLE who receive IVIG therapy, the evidence includes an RCT, multiple observational studies, and a meta-analysis. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Although observed improvements in outcomes have suggested potential benefit with IVIG therapy for surrogate outcomes, data are retrospective. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have immune optic neuritis who receive IVIG therapy, the evidence includes two RCTs. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show improvements in vision-related outcomes. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have Crohn disease who receive IVIG therapy, the evidence includes multiple case reports of single patients summarized in a systematic review. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, treatment-related mortality and treatment-related morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have hemophagocytic lymphohistiocytosis who receive IVIG therapy, the evidence includes multiple case reports summarized in a systematic review. The relevant outcomes are OS,DSS, change in disease status, QOL, and treatment-related mortality and morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have warm antibody autoimmune hemolytic anemia, refractory to prednisone and splenectomy, who receive IVIG therapy, the evidence includes pooled observational data. The relevant outcomes are a change in disease status, QOL, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested potential benefits with IVIG therapy in select patients. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have antiphospholipid syndrome who receive IVIG therapy, the evidence includes pooled data from a registry. The relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested potential mortality benefit with IVIG therapy. RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Alloimmune Processes
For individuals who have neonatal alloimmune thrombocytopenia who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. The relevant outcomes are DSS, change in disease status, and treatment-related mortality and morbidity. Compared with combination use with corticosteroids, IVIG alone did not show any additional increases in platelet counts. Multiple trials have demonstrated increased platelet counts with IVIG therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have are current spontaneous abortion who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. The relevant outcomes are DSS, treatment-related mortality, and treatment-related morbidity. In multiple RCTs, compared with placebo, IVIG therapy alone did not show any beneficial effects in preventing spontaneous abortions. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

Miscellaneous Indications
For individuals who have PANDAS who receive IVIG therapy, the evidence includes two small RCTs. The relevant outcomes are symptoms, change in disease status, and treatment-related mortality and morbidity. The trials had mixed findings and both had small sample sizes and short intervention duration. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have autism spectrum disorder who receive IVIG therapy, the evidence includes case series. The relevant outcomes are symptoms, change in disease status, functional outcomes, health status measures, QOL, treatment-related mortality and treatment-related morbidity. Although improvements were observed in one case series, the other two reported negative findings. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have CRPS who receive IVIG therapy, the evidence includes an RCT. The relevant outcomes are symptoms, morbid events, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown improvements in pain scores. However, methodologic limitations restrict the conclusions drawn from data on 12 patients. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have AD who receive IVIG therapy, the evidence includes three RCTs. The relevant outcomes are OS, DSS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. With the exception of a few subgroup analyses using MCI status, IVIG therapy was not significantly better than a placebo for outcomes such as brain atrophy, level of plasma amyloid β 1-40, or cognition and function. Studies differed by treatment protocols, outcomes assessed, and two of the three had relatively small sample sizes. Additional RCTs could be conducted to confirm whether IVIG benefits patients with early MCI. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have paraproteinemic neuropathy who receive IVIG therapy, the evidence includes two small RCTs. The relevant outcomes are a change in disease status, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG showed mild and transitory improvements in one trial but failed to show any improvement in another. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have chronic fatigue syndrome who receive IVIG therapy, the evidence includes an RCT and anecdotal reports. The relevant outcomes are symptoms, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown no therapeutic benefits. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have acute myocarditis who receive IVIG therapy, the evidence includes an RCT, a quasi-randomized trial, and multiple case reports. The relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy failed to show improvements in event-free survival in the RCT while it showed favorable effects on rates of event-free survival in a quasi-randomized study. However, both studies were rated as very low quality and at a high-risk of bias. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have refractory recurrent pericarditis who receive IVIG therapy, the evidence includes multiple case reports and case series. The relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Although improvements were observed in some patients, controlled trials are lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have stiff-person syndrome who receive IVIG therapy, the evidence includes an RCT and multiple case reports. The relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown decreases in stiffness scores and improvements in functional outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have noninfectious uveitis who receive IVIG therapy, the evidence includes two small case series. The relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. The case series (total n = 28 patients) reported measurable improvements in visual acuity after IVIG therapy, but controlled studies are needed to draw conclusions about the efficacy of IVIG for this population. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have postpolio syndrome who receive IVIG therapy, the evidence includes multiple RCTs, prospective studies, and a meta-analysis. The relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show reductions in the severity of pain and fatigue or improvements in muscle strength. The evidence is sufficient to determine that the technology is unlikely to improve the net health outcome.

For individuals who have necrotizing fasciitis who receive IVIG therapy, the evidence includes an RCT. The relevant outcomes are OS, symptoms, functional outcomes, and treatment-related mortality and morbidity. The RCT found that, compared with placebo, IVIG therapy did not significantly improve functional outcomes, mortality rates, or other outcomes (e.g., the use of life support in the intensive care unit). Additional controlled studies are needed to draw conclusions about the efficacy of IVIG for treating necrotizing fasciitis. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 3 physician specialty societies and 5 academic medical centers in March 2013 after this policy was under review in 2012. Input focused on intravenous immunoglobulin (IVIG) treatment for seven rare conditions. There was consensus, or near-consensus, that IVIG is investigational for six of these conditions: birdshot retinopathy, epidermolysis bullosa acquisita, necrotizing fasciitis, opsoclonus-myoclonus, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, and polyradiculoneuropathy (other than chronic inflammatory demyelinating polyneuropathy). Clinical input was mixed overall on the seventh condition, IVIG for treating severe anemia associated with parvovirus B19.

Additional clinical input was obtained in June 2013, focusing on severe anemia due to parvovirus B19. Input was received from three reviewers (all hematologists), and there was a consensus that IVIG is not investigational for this indication. There was a lack of consensus among the 3 reviewers on any specific clinical or patient characteristics that can be used to select patients with severe anemia due to parvovirus B19 for treatment with IVIG and on any treatments that should be used by these patients before IVIG.

Practice Guidelines and Position Statements
Immunodeficiency States
Primary Humoral Immune Deficiencies
National Advisory Committee on Blood and Blood Products and Canadian Blood Services
The National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services (CBS) (2010) published guidelines on the use of immunoglobulin therapy for patients with primary immune deficiency.² The guidelines reported that there was sufficient evidence that immunoglobulin therapy reduces the rate of infection and hospitalization in patients with primary immune deficiency, lowers mortality, and improves quality of life. Treatment should be started at a dose of 400 to 600 mg/kg per 4 weeks for IVIG or 100 to 150 mg/kg per week for subcutaneous immunoglobulin infusion.

American Academy of Allergy, Asthma, and Immunology
The American Academy of Allergy, Asthma, and Immunology (2015) published practice parameters for the diagnosis and management of primary immunodeficiency.¹⁴⁰ The Academy advised that treatment of these conditions include antibiotic prophylaxis and immunoglobulin G (IgG) replacement.

Hematopoietic Cell Transplantation (Prophylaxis)
The NAC and CBS (2007) published guidelines on the use of IVIG for hematologic conditions.⁴⁰ The guidelines stated that evidence does not support the use of IVIG after hematopoietic cell transplantation.

Acute Antibody-Mediated Rejection After Solid Organ Transplant
The CBS and NAC (2010) developed guidelines addressing the use of IVIG for sensitized individuals undergoing solid organ transplantation.¹⁴¹ The following conclusions were issued on nonkidney solid organ transplantation:

• For patients undergoing heart transplantation, to improve graft/overall survival or to treat rejection: insufficient evidence to recommend for or against the routine use of IVIG (however, other factors may influence decision-making)
• For desensitization for patients undergoing lung transplantation or for the treatment of rejection: insufficient evidence to make a recommendation for or against the routine use of IVIG (however, other factors may influence decision-making)
• For patients undergoing liver transplantation or for the treatment of rejection/ABO-incompatible liver transplantation: insufficient evidence to make a recommendation for or against the routine use of IVIG
• For the use of IVIG for solid organ transplantation: limited methodologically rigorous evidence
• Future studies are needed to delineate the effect of IVIG on desensitization using standardized methods for desensitization; the effect of IVIG on acute rejection rates, graft survival, and overall survival; the use of the combined modality IVIG and plasmapheresis compared either to plasmapheresis or IVIG alone; and the optimum dosage of IVIG.

Chronic Lymphocytic Leukemia
The National Comprehensive Cancer Network guidelines (v.1.2020 ) on chronic lymphocytic leukemia recommend IVIG as supportive care for patients with chronic lymphocytic leukemia: for the treatment of autoimmune cytopenias and recurrent sinopulmonary infections (IgG levels < 500 mg/dL).¹⁴² The guidelines recommend monitoring IVIG levels and administering monthly IVIG (0.3 – 0.5 g/kg) to maintain levels of 500 mg/dL.

Infections
Infections in HIV-Infected Children
In 2018, updated joint guidelines on the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children.²⁶ The guidelines, endorsed by the American Academy of Pediatrics, the Infectious Diseases Society of America, and other agencies and societies, included the following statements:

• “Intravenous immune globulin is recommended to prevent serious bacterial infections in HIV-infected children who have hypogammaglobulinemia.”
• "In rare situations in which cART and antibiotic prophylaxis are not effective in preventing frequent recurrent serious bacterial infections, IVIG prophylaxis can be considered for secondary prophylaxis."

Neonatal Sepsis
The American Academy of Pediatrics (2018) published guidelines on the management of neonates with suspected or proven early-onset bacterial sepsis.¹⁴³ The guidelines did not address the use of IVIG to treat neonatal sepsis.

Autoimmune and Inflammatory Conditions
Idiopathic Thrombocytopenic Purpura
The NAC and CBS (2007) issued guidelines on the use of IVIG for hematologic conditions, including idiopathic thrombocytopenic purpura (ITP).⁴⁰ Recommendations for patients with ITP are as follows:

• Adult acute ITP with bleeding: IVIG strongly recommended as a part of multimodality therapy for major or life-threatening bleeding complications and/or clinically important mucocutaneous bleeding.
• Adult acute ITP with severe thrombocytopenia but no bleeding: IVIG not recommended as first-line therapy alone, except for patients with contraindications to corticosteroids.
• Adult ITP with no or slow response to adequate dose corticosteroids: IVIG may be considered as a possible adjunctive therapy.
• Adult chronic ITP postsplenectomy: IVIG may be considered as a possible adjunctive therapy as a corticosteroid-sparing measure. The minimal dose of IVIG should be used that maintains a safe platelet count. Patients should be reevaluated every three to six months, and alternative therapies to IVIG should be considered for patients who do not achieve a durable response for a minimum of two to three weeks.

Guillain-Barré Syndrome
The American Academy of Neurology (AAN; 2012) guidelines on the treatment of neuromuscular disorders concluded that IVIG is as efficacious as plasmapheresis and should be offered as a treatment option to adults with Guillain-Barré syndrome (level A).⁵⁹ The guidelines indicated that there was insufficient evidence to support or refute the use of IVIG in children.

The European Federation of Neurological Societies (EFNS; 2008) issued guidelines on the use of IVIG for the treatment of neurologic disorders.¹⁴⁴ The guidelines stated that the efficacy of IVIG treatment of Guillain-Barré syndrome has been established (level A).

Kawasaki Syndrome and Other Vasculitides
The American Academy of Family Physicians (2015)¹⁴⁵ and the American Heart Association (2004)¹⁴⁶ have supported the use of IVIG in the treatment of Kawasaki syndrome.

Chronic Inflammatory Demyelinating Polyneuropathy
The AAN (2012) guidelines on the treatment of neuromuscular disorders stated that IVIG is effective and should be offered as a long-term treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) (level A).⁵⁹ The guidelines indicated that data are insufficient to compare the efficacy of prednisone and IVIG in the treatment of CIDP.

The EFNS (2008) issued guidelines on the use of IVIG for the treatment of neurologic disease.¹⁴⁴ The guidelines indicated that the efficacy of IVIG for the treatment of CIDP has been established (level A).

The EFNS and the Peripheral Nerve Society (2010) published guidelines on the management of chronic inflammatory demyelinating polyradiculoneuropathy.¹⁴⁷ “Intravenous immunoglobulin (IVIg) (Recommendation Level A) or corticosteroids (Recommendation Level C) should be considered in sensory and motor CIDP in the presence of disabling symptoms,” and “IVIg should be considered as the initial treatment in pure motor CIDP (Good Practice Point).”

Multifocal Motor Neuropathy
The AAN (2012) guidelines on the treatment of neuromuscular disorders stated that IVIG is probably effective and should be considered for the treatment of multifocal motor neuropathy (level B).⁵⁹ There were insufficient data to determine the optimal treatment interval, dosing, and duration.

The EFNS (2008) issued guidelines on the use of IVIG for the treatment of neurologic disorders.¹⁴⁴ The guidelines indicated that the efficacy of IVIG for the treatment of multifocal motor neuropathy has been established (level A).

Eaton-Lambert Myasthenic Syndrome
The AAN (2012) guidelines on the treatment of neuromuscular disorders stated that IVIG is possibly effective and may be considered for treating Lambert-Eaton myasthenic syndrome (level C).⁵⁹

Neuromyelitis Optica
According to the Neuromyelitis Optica’s (2014) updated guidelines, high-dose IVIG is potentially beneficial in the long-term treatment of neuromyelitis optica and may be used as an alternative for patients with a contraindication to one of the other treatments or, particularly, in children.¹⁴⁸

Severe Refractory Myasthenia Gravis or Myasthenic Exacerbation
The AAN (2012) guidelines on the treatment of neuromuscular disorders concluded that IVIG therapy is probably effective in treating patients with severe myasthenia gravis and should be considered in the treatment plan (level B).⁵⁹ There was insufficient evidence to compare IVIG and plasmapheresis in the treatment of these patients.

The EFNS (2008) issued guidelines on the use of IVIG to treat neurologic disorders.¹⁴⁴ The guidelines indicated that the efficacy of IVIG for the treatment of acute exacerbations of myasthenia gravis and short-term treatment of severe myasthenia gravis has been established (level A).

Relapsing-Remitting Multiple Sclerosis
The AAN (2002) published a technology assessment on therapies for multiple sclerosis.⁷⁹ The assessment was reviewed and reaffirmed in 2018. The assessment offered the following recommendations on IVIG:

• Studies of IVIG to date have generally involved small numbers of patients, have lacked complete data on clinical and MRI (magnetic resonance imaging) outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIG reduces the attack rate in relapsing-remitting multiple sclerosis (type C recommendation: possibly effective, ineffective, or harmful).
• Current evidence suggests that IVIG is of little benefit with regard to slowing disease progression (type C recommendation: possibly effective, ineffective, or harmful).

The EFNS (2008) issued guidelines on the use of IVIG for the treatment of neurologic disorders.^144,The guidelines recommended IVIG as second- or third-line therapy for relapsing-remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B).

Autoimmune Mucocutaneous Blistering Diseases
There are currently no guidelines specific to the treatment of autoimmune mucocutaneous blistering disease.

Toxic Epidermal Necrosis and Stevens-Johnson Syndrome
The British Association of Dermatologists (2016) published guidelines on the management of toxic epidermal necrosis and Stevens-Johnson syndrome in adults.¹⁴⁹ These guidelines are accredited by the National Institute for Health and Care Excellence. The guidelines indicated that evidence for the use of IVIG in the treatment of toxic epidermal necrosis and Stevens-Johnson syndrome was not of sufficient quality or consistency.

The British Association of Dermatologists(2019) published guidelines for the management of Stevens-Johnson syndrome and toxic epidermal necrolysis in children and young people, which said, “There is no reliable evidence on the benefits or lack of benefit of any systemic treatments including prednisolone, IVIg, anti-tumor necrosis factor (TNF) biologics or ciclosporin.”¹⁵⁰

Idiopathic Inflammatory Myopathies
The AAN (2012) guidelines on IVIG for treating neuromuscular disorders have stated that IVIG is possibly effective and may be considered as a treatment for nonresponsive dermatomyositis (an idiopathic inflammatory condition) in adults (level C).⁵⁹

The EFNS issued guidelines in 2008 on the use of IVIG for treating neurologic disorders.¹⁴⁴ The guidelines recommended IVIG in combination with prednisone as a second-line treatment for dermatomyositis (level B).

Immune Optic Neuritis
Optic neuritis presents as a manifestation of multiple sclerosis (see the Relapsing-Remitting Multiple Sclerosis section above).

Alloimmune Processes
Neonatal Alloimmune Thrombocytopenia
The NAC and CBS (2007) published guidelines on the use of IVIG for hematologic conditions.⁴⁰

• Treatment of fetus: Evidence is limited and weak, but given that the condition is rare and the consequences are serious, IVIG was deemed an appropriate option and should be considered the standard of care.
• Treatment of newborn: First-line therapy should be antigen-negative compatible platelets, with IVIG considered as adjunctive therapy.

Recurrent Spontaneous Abortion
The Royal College of Obstetricians and Gynecologists (2011) issued guidelines on the treatment of recurrent first- and second-trimester miscarriages.¹⁵¹ The guidelines, accredited by the National Institute for Health and Care Excellence, concluded that IVIG does not improve the live birth rate in women with recurrent miscarriages (level A).

Miscellaneous
Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections
The NAC and CBS (2007) convened a panel of national experts to develop evidence-based practice guidelines on the use of IVIG for neurologic conditions.¹⁵² The panel recommended the use of IVIG for the treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. The optimal dose and duration of treatment are uncertain.

Autism Spectrum Disorder
The NAC and CBS (2007) guidelines on neurologic conditions did not recommend IVIG for autism.¹⁵²

The American Academy of Child and Adolescent Psychiatry (2014) published practice parameters on the assessment and treatment of autism spectrum disorder.¹⁵³ The Academy parameters did not address the use of IVIG for the treatment of autism spectrum disorder.

Chronic Fatigue Syndrome
The National Institute for Health and Care Excellence (2007) issued guidance on the diagnosis and management of chronic fatigue syndrome.¹⁵⁴ The guidance was reviewed in 2014, and no changes to the recommendations were made at that time. The guidance indicated that there is no cure for chronic fatigue syndrome and that symptoms (pain, sleep disturbances, physical limitations, and debilitating fatigue) should be managed under the supervision of a specialist. The use of IVIG was not addressed.

Viral Myocarditis
The American College of Cardiology Foundation and the American Heart Association issued joint guidelines in 2013, updated in 2017, on the management of heart failure.¹⁵⁵ The guidelines did not address the use of IVIG for the treatment of viral myocarditis.

Stiff Person Syndrome
The EFNS (2008) issued guidelines on the use of IVIG for the treatment of neurologic disorders.¹⁴⁴ The guidelines indicated that IVIG seems to have a favorable effect in the treatment of stiff person syndrome (level A).

Postpolio Syndrome
The EFNS updated its guidelines on the definition and management of postpolio syndrome in 2011.¹⁵⁶ The guidelines indicated that IVIG could have a modest therapeutic effect on the postpolio syndrome, though there were limitations to the study evidence (small sample size, inadequate comparators, appropriate dosage). Due to these limitations, EFNS concluded that IVIG cannot be recommended as a standard treatment.

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable 

ONGOING AND UNPUBLISHED CLINICAL TRIALS

Table 1. Summary of Key Trials 

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03065244	KIDCARE (Kawasaki Disease Comparative Effectiveness Trial)	250	Sep 2020
NCT02176863a	A Multicenter, Prospective, Randomized, Placebo-controlled, Double-blind, Parallel-Group Clinical Trial to Assess the Efficacy and Safety of Immune Globulin Intravenous (Human) Flebogamma® 5% DIF in Patients With Post-Polio Syndrome	210	Jun 2021
NCT03194815	IVIG and Rituximab in Antibody-associated Psychosis - SINAPPS2 (SINAPPS2)	80	Dec 2021
NCT02899702	Effectiveness of Intravenous Immunoglobulins (IVIG) in Toxic Shock Syndromes in Children	156	Apr 2022
Unpublished
NCT00892112a	Immunoglobulin Therapy for Patients With Idiopathic Cardiomyopathy and Endomyocardial Parvovirus B19 Persistence - a Prospective, Double-blind, Randomized, Placebo-controlled Clinical Trial	50	Jun 2018 (completed)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.  

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110. Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev. Apr 19 2006(2):CD000112. PMID 16625529
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112. Wang SW, Zhong SY, Lou LJ, et al. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis. Reprod Biomed Online. Dec 2016;33(6):720-736. PMID 27720163
113. Christiansen OB, Pedersen B, Rosgaard A, et al. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod. Mar 2002;17(3):809-816. PMID 11870141
114. Branch DW, Peaceman AM, Druzin M, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol. Jan 2000;182(1 Pt 1):122-127. PMID 10649166
115. Jablonowska B, Selbing A, Palfi M, et al. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Hum Reprod. Mar 1999;14(3):838-841. PMID 10221723
116. 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. Oct 2016;55(10):860-867.e862. PMID 27663941
117. Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. Oct 2 1999;354(9185):1153-1158. PMID 10513708
118. Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. Aug 1996;26(4):439-452. PMID 8863094
119. Plioplys AV. Intravenous immunoglobulin treatment of children with autism. J Child Neurol. Feb 1998;13(2):79- 82. PMID 9512308
120. DelGiudice-Asch G, Simon L, Schmeidler J, et al. Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. J Autism Dev Disord. Apr 1999;29(2):157-160. PMID 10382136
121. Goebel A, Bisla J, Carganillo R, et al. Low-dose intravenous immunoglobulin treatment for long-standing complex regional pain syndrome: a randomized trial. Ann Intern Med. Oct 3 2017;167(7):476-483. PMID 28973211
122. Goebel A, Baranowski A, Maurer K, et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med. Feb 2 2010;152(3):152-158. PMID 20124231
123. Relkin NR, Thomas RG, Rissman RA, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology. May 02 2017;88(18):1768-1775. PMID 28381506
124. Kile S, Au W, Parise C. IVIG treatment of mild cognitive impairment due to Alzheimer's disease: a randomised double-blinded exploratory study of the effect on brain atrophy, cognition and conversion to dementia. Feb 2017;88(2):106-112. PMID 26420886
125. Dodel R, Rominger A, Bartenstein P, et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. Mar 2013;12(3):233-243. PMID 23375965
126. Comi G, Roveri L, Swan A, et al. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol. Oct 2002;249(10):1370-1377. PMID 12382151
127. Dalakas MC, Quarles RH, Farrer RG, et al. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol. Nov 1996;40(5):792-795. PMID 8957021
128. Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, et al. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med. Jul 1997;103(1):38-43. PMID 9236484
129. Robinson J, Hartling L, Vandermeer B, et al. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. May 20 2015(5):CD004370. PMID 25992494.
130. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation. May 8 2001;103(18):2254-2259. PMID 11342473
131. Bhatt GC, Sankar J, Kushwaha KP. Use of intravenous immunoglobulin compared with standard therapy is associated with improved clinical outcomes in children with acute encephalitis syndrome complicated by myocarditis. Pediatr Cardiol. Dec 2012;33(8):1370-1376. PMID 22588459
132. 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. doi: 10.1536/ihj.18-299. Epub 2019 Feb 8. PMID: 30745539
133. Heidendael JF, Den Boer SL, Wildenbeest JG, et al. Intravenous immunoglobulins in children with new onset dilated cardiomyopathy. Cardiol Young. Jan 2018;28(1):46-54. PMID 28797313
134. 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 (Hagerstown). Apr 2016;17(4):263-269. PMID 26090917
135. Dalakas MC, Fujii M, Li M, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. Dec 27 2001;345(26):1870-1876. PMID 11756577
136.  LeHoang P, Cassoux N, George F, et al. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocul Immunol Inflamm. Mar 2000;8(1):49-57. PMID 10806434
137. Rosenbaum JT, George RK, Gordon C. The treatment of refractory uveitis with intravenous immunoglobulin. Am J Ophthalmol. May 1999;127(5):545-549. PMID 10334347
138. Huang YH, Chen HC, Huang KW, et al. Intravenous immunoglobulin for postpolio syndrome: a systematic review and meta-analysis. BMC Neurol. Mar 22 2015;15:39. PMID 25886512
139. Madsen MB, Hjortrup PB, Hansen MB, et al. Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT): a randomised, blinded, placebo-controlled trial. Intensive Care Med. Nov 2017;43(11):1585-1593. PMID 28421246
140. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. Nov 2015;136(5):1186-1205 e1181-1178. PMID 26371839
141. Shehata N, Palda VA, Meyer RM, et al. The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline. Transfus Med Rev. Jan 2010;24(Suppl 1):S7-S27. PMID 19962580
142. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed September 1, 2019.
143. Polin RA, Committee on Fetus Newborn. Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics. https://pediatrics.aappublications.org/content/pediatrics/142/6/e20182894.full.pdf. Accessed August 5, 2019.
144. 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. Sep 2008;15(9):893-908. PMID 18796075
145. Saguil A, Fargo M, Grogan S. Diagnosis and management of Kawasaki disease. Am Fam Physician. Mar 15 2015;91(6):365-371. PMID 25822554
146. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. Oct 26 2004;110(17):2747-2771. PMID 15505111
147. Van den Bergh PYK, Hadden RDM, Bouche P, et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - First Revision. Eur J Neurol. 2010;17:356-363. doi: 10.1111/j.1468-1331.2009.02930.x. https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1468-1331.2009.02930.x. Accessed August 5, 2019.
148. Trebst C, Jarius S, Berthele A, et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. Jan 2014;261(1):1-16. PMID 24272588
149. Creamer D, Walsh SA, Dziewulski P, et al. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol. Jun 2016;174(6):1194-1227. PMID 27317286
150. McPherson T, Exton LS, Biswas S, et al. British Association of Dermatologists' guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in children and young people, 2018. Br J Dermatol. 2019;181:37-54. doi: 10.1111/bjd.17841. https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.17841. Accessed August 5, 2019.
151. Royal College of Obstetricians and Gynecologists. The Investigation and Treatment of Couples with Recurrent Firsttrimester and Second-trimester Miscarriage. Royal Colleg of Obstetricians and Gynecologists Green-Top Guidelines No. 17. 2011; https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf. Accessed September 1, 2019.
152. Feasby T, Banwell B, Benstead T, et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev. Apr 2007;21(2 Suppl 1):S57-107. PMID 17397768
153. Volkmar F, Siegel M, Woodbury-Smith M, et al. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. Feb 2014;53(2):237-257. PMID 24472258
154. National Institute for Health and Care Excellence (NICE). Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management [CG53]. 2007; https://www.nice.org.uk/guidance/cg53. Accessed September 1, 2019.
155. Writing Committee Members, Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation.http://www.onlinejacc.org/content/accj/62/16/e147.full.pdf?_ga=2.263134286.333447317.1567091133-1492977278.1567091133. Accessed August 5, 2019.
156. Farbu E, Gilhus NE, Barnes MP, et al. Chapter 18: Post-polio syndrome. In: Gilhus NE, Barnes MP, Brainin M, eds. European Handbook of Neurological Management: Volume 1, 2nd Edition. Hoboken, NJ: Blackwell Publishing; 2011.
157. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination for intravenous immune globulin for the treatment of autoimmune mucocutaneous blistering diseases (250.3). 2002; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCDId=158&ncdver=1&CoverageSelection=National&KeyWord=globulin&KeyWordLookUp=Title& KeyWordSearchType=And&bc=gAAAABAAAAAA&. Accessed September 1, 2019. 

Coding Section

Codes	Number	Description
CPT	90283	Immune globulin (IgIV), human, for intravenous use
	90284	Immune globulin (SCIg), human, for use in subcutaneous infusions, 100 mg, each
	96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
	96366	each additional hour (List separately in addition to code for primary procedure)
	96369	Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); initial, up to one hour, including pump set-up and establishment of subcutaneous infusion site(s)
	96370	each additional hour (List separately in addition to code for primary procedure)
	96371	additional pump set-up with establishment of new subcutaneous infusion site(s) (List separately in addition to code for primary procedure)
HCPCS	J1459	Injection, immune globulin (Privigen), intravenous, non-lyophilized (e.g., liquid), 500 mg
	J1554 (effective 04/01/2021)	Injection, immune globulin (asceniv), 500 mg
	J1555 (effective 1/1/2018)	Injection, immune globulin (cuvitru), 100 mg
	J1556	Injection, immune globulin (Bivigam), 500 mg
	J1557	Injection, immune globulin (Gammaplex), intravenous, non-lyophilized (e.g., liquid), 500 mg
	J1558 (effecitve 7/1/2020)	Injection, immune globulin (Xembify), 100 mg
	J1559	Injection, immune globulin (Hizentra), 100 mg
	J1561	Injection, immune globulin (Gamunex-C/Gammaked), non-lyophilized (e.g., liquid), 500 mg
	J1562	Injection, immune globulin (Vivaglobin), subcutaneous, 100 mg
	J1566	Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg
	J1568	Injection, immune globulin (Octagam) intravenous, non-lyophilized (e.g., liquid), 500 mg
	J1569	Injection, immune globulin (Gammagard Liquid) intravenous, non-lyophilized (e.g., liquid), 500 mg
	J1572	Injection, immune globulin (Flebogamma/Flebogamma DIF), intravenous, non-lyophilized (e.g., liquid), 500 mg
	J1575	Injection, immune globulin/hyaluronidase, (Hyqvia), 100 mg immune globulin
	J1576	Injection, immune globulin (Panzyga), intravenous, non-lyophilized (e.g., liquid), 500mg (effective 7/1/2023)
	J1599	Injection, immune globulin, intravenous, non-lyophilized (e.g., liquid), not otherwise specified, 500 mg
ICD-10-CM (effective 10/01/15)	A40.0-A40.9	Streptococcal sepsis, code range
	A41.01- A41.9	Other sepsis, code range
	A48.3	Toxic shock syndrome
	B20	HIV
	B34.3	Parvovirus infection, unspecified
	B95.0-B95.8	Streptococcus, staphylococcus and enterococcus as the cause of diseases classified elsewhere code range
	B97.6	Parvovirus as the cause of diseases classified elsewhere
	C91.10-C91.12	Chronic lymphocytic leukemia of b-cell type
	D59.1	Other autoimmune hemolytic anemias (includes warm type)
	D68.61	Anticardiolipin syndrome (includes antiphospholipid syndrome)
	D80.0-D80.9	Immunodeficiency with predominantly antibody defects
	D82.0-D82.9	Immunodeficiency associated with other major defects (includes Wiskott-Aldrich syndrome)
	D83.0-D83.9	Common variable immunodeficiency
	G11.3	Cerebellar ataxia with defective DNA repair (includes ataxia telangiectasia)
	G25.82	Stiff-man syndrome
	G35	Multiple sclerosis
	G60.00-G60.9	Hereditary and idiopathic neuropathy
	G61.0	Guillain-Barre syndrome
	G61.81	Chronic inflammatory demyelinating polyneuritis
	G61.82	Multifocal motor neuropathy
	G70.01	Myasthenia gravis with (acute) exacerbation
	G73.3	Myasthenic syndromes in other diseases classified elsewhere
	I44.0-I45.9	Other conduction disorders
	L10.0-L10.9	Pemphigus code range
	L12.0-L12.9	Pemphigoid code range
	L51.3	Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome
	M30.3	Mucocutaneous lymph node syndrome
	M31.30-M31.31	Wegener's granulomatosis
	M33.20-M33.29	Polymyositis code range
	M33.90-M33.99	Dermatopolymyositis unspecified
	P.07.00-P07.39	Disorders of newborn related to short gestation and low birth weight, not elsewhere classified code range
	P36.0-P36.9	Bacterial sepsis of newborn, code range
	P61.0	Transient neonatal thrombocytopenia
	Z94.81	Bone marrow transplant status
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.
	3E013GC	Administration, introduction, subcutaneous tissue, percutaneous, other therapeutic substance
	3E033GC	Administration, introduction, peripheral vein, percutaneous other therapeutic substance
	3E033WK, 3W033WL	Administration, introduction, peripheral vein, immunotherapeutic, code by qualifier (immunostimulator or immunosuppressive)
Type of Service	Therapy
Place of Service	Physician Office

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

Appendix
Appendix A:
Diagnostic Criteria for Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

The following criteria are adapted from the Task Force Report of the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. (Neurology 1991; 41(5):617 – 8) The report included mandatory, supportive, and exclusionary diagnostic criteria. Only the mandatory criteria are excerpted here. The criteria are based on a combination of clinical observations, physiologic studies, pathologic features (i.e., nerve biopsy), and studies of the cerebrospinal fluid (CSF).

I. Clinical
Mandatory

1. Progressive or relapsing motor and sensory, rarely only motor or sensory, dysfunction of more than 1 limb or a peripheral nerve nature, developing over at least 2 months.
2. Hypo- or are flexia. This will usually involve all 4 limbs.

II. Physiologic Studies
Mandatory

Nerve conduction studies including studies of proximal nerve segments in which the predominant process is demyelination.

Must have 3 of 4:

1. Reduction in conduction velocity (CV) in 2 or more motor nerves:

1. < 80% of lower limit of normal (LLN) is amplitude > 80% of LLN
2. < 70% of LLN is amplitude < 80% of LLN

2. Partial conduction block or abnormal temporal dispersion in 1 or more motor nerves: either peroneal nerve between ankle and below fibular head, median nerve between wrist and elbow, or ulnar nerve between wrist and below elbow.

Criteria suggestive of partial conduction block: < 15% change in duration between proximal and distal sites and >20% drop in negative peak (p) area or peak to peak (p-p) amplitude between proximal and distal sites.

Criteria for abnormal temporal dispersion and possible conduction block: > 15% change in duration between proximal and distal sites and > 20% drop in p area or p-p amplitude between proximal and distal sites and > 20% drop in p or p-p amplitude between proximal and distal sites. These criteria are only suggestive of partial conduction block as they are derived from studies of normal individuals. Additional studies, such as stimulation across short segments or recording of individual motor unit potentials, are required for confirmation.

3. Prolonged distal latencies in 2 or more nerves:

1. > 125% of upper limit of normal (LEN) is amplitude > 80% of LLN
2. > 150% of LEN if amplitude < 80% of LLN.

4. Absent F waves or prolonged minimum

1. > 120% of ULN if amplitude > 80% of LLN
2. > 150% of ULN if amplitude < 80% of LLN.

III. Pathologic Features
Mandatory

Nerve biopsy showing unequivocal evidence of demyelination and remyelination.

Demyelination by either electron microscopy (> 5 fibers) or teased fiber studies > 12% of 50 fibers, minimum of 4 internodes each, demonstrating demyelination/remyelination.

IV. CSF Studies
Mandatory

1. Cell count < 10 per cubic mm if HIV-seronegative or < 50 per cubic mm is HIV seropositive
2. Negative VDRL

The following criteria are adapted from the Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst. 2005;10:220 – 228. The EFNS/PNS diagnostic criteria were designed to balance specificity and sensitivity.

I. Inclusion Criteria

1. Typical CIDP — Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least 2 months; cranial nerves may be affected; and absent or reduced tendon reflexes in all extremities
2. Atypical CIDP

One of the following, but otherwise as in typical CIDP (tendon reflexes may be normal in unaffected limbs):

• Predominantly distal weakness (distal acquired demyelinating symmetric, DADS)
• Pure motor or sensory presentations, including chronic sensory immune polyradiculoneuropathy affecting the central process of the primary sensory neuron
• Asymmetric presentations (multifocal acquired demyelinating sensory and motor, MADSAM, Lewis-Sumner syndrome
• Focal presentations (e.g., involvement of the brachial plexus or of one or more peripheral nerves in one upper limb
• Central nervous system involvement (may occur with otherwise typical or other forms of atypical CIDP)

II. Exclusion Criteria

• Diphtheria, drug or toxin exposure likely to have caused the neuropathy
• Hereditary demyelinating neuropathy, known or likely because of family history, foot deformity, mutilation of hands or feet, retinitis pigmentosa, ichthyosis, liability to pressure palsy
• Presence of sphincter disturbance
• Multifocal motor neuropathy
• Antibodies to myelin-associated glycoprotein

III. Electrodiagnostic Criteria
1. Definite

At least one of the following:

• At least 50% prolongation of motor distal latency above the upper limit of normal values in two nerves, or
• At least 30% reduction of motor conduction velocity below the lower limit of normal values in two nerves, or
• At least 20% prolongation of F-wave latency above the upper limit of normal values in two nerves (> 50% if amplitude of distal negative peak CMAP, 80% of lower limit of normal values), or
• Absence of F-waves in two nerves if these nerves have amplitudes of distal negative peak CMAPs at least 20% of lower limit of normal values + at least one other demyelinating parameter* in at least one other nerve, or
• Partial motor conduction block: at least 50% amplitude reduction of the proximal negative peak CMAP relative to distal, if distal negative peak CMAP at least 20% of lower limit of normal values, in two nerves, or in one nerve + at least one other demyelinating parameter* in at least one other nerve, or
• Abnormal temporal dispersion (> 30% duration increase between the proximal and distal negative peak CMAP) in at least two nerves, or
• Distal CMAP duration (interval between onset of the first negative peak and return to baseline of the last negative peak) of at least 9 ms in at least one nerve + at least one other demyelinating parameter* in at least one other nerve

2. Probable

At least 30% amplitude reduction of the proximal negative peak CMAP relative to distal, excluding posterior tibial nerve, if distal negative peak CMAP at least 20% of lower limit of normal values, in two nerves, or in one nerve + at least one other demyelinating parameter* in at least one other nerve

3. Possible

As in (1) but in only one nerve

CMAP, compound muscle action potential. To apply these criteria, the median, ulnar (stimulated below the elbow), peroneal (stimulated below the fibular head), and tibial nerves on one side are tested. Temperatures should be maintained at least 33° C at the palm and 30° C at the external malleolus (good practice points).

* Any nerve meeting any of the criteria

IV. Supportive Criteria

Elevated cerebrospinal fluid protein with leukocyte < 10/mm3 (level A recommendation)

Magnetic resonance imaging showing gadonlinium enhancement and /or hypertrophy of the cauda equine, lumbosacral or cervical nerve roots, or the brachial or lumbosacral plexus (level C recommendation)

Nerve biopsy showing unequivocal evidence of demyelination and/or remyelination in > 5 fibers by electron microscopy or in > 6 of 50 teased fibers

Clinical improvement following immunomodulatory treatment (level A recommendation)

Appendix B:
Diagnostic Criteria for Diagnosis of Multifocal Motor Neuropathy (MMN)

The following are proposed diagnostic criteria adapted from a 2005 article by Van Asseldonk and colleagues (Lancet Neurology; 4: 309 – 319)

I. Clinical criteria

1. Slow or stepwise progressive limb weakness
2. Asymmetrical limb weakness
3. Fewer than seven affected limb regions (on each side: upper arm, lower arm, upper leg, or lower leg)
4. Tendon reflexes in affected limbs are decreased or absent
5. Signs and symptoms more pronounced in arms than in legs
6. 20 – 65 years old at disease onset
7. No objective sensory abnormalities except for vibration sense
8. No bulbar signs or symptoms
9. No upper-motor-neuron features
10. No other neuropathies
11. No myopathy (e.g., dystrophy, inclusion-body myositis)

II. Laboratory criteria

1. CSF protein less than 1 g/L
2. High anti-GM1 titre
3. High signal intensity on T2-weighted MRI of the brachial plexus

III. Electrodiagnostic criteria

1. Definite motor conduction block: Compound muscle action potential (CMAP) area reduction on proximal versus distal stimulation of at least 50% over a long segment (between erb and axilla, upper arm, lower arm, lower leg), or a CMAP amplitude reduction on proximal versus distal stimulation of at least 30% over a short distance (2·5 cm) detected by inching. CMAP amplitude on stimulation of the distal part of the segment with motor conduction block of at least 1 mV
2. Probably motor conduction block: CMAP amplitude reduction on proximal versus distal stimulation of at least 30% over a long segment of an arm nerve. CMAP amplitude on stimulation of the distal part of the segment with motor conduction block of at least 1 mV
3.  Slowing of conduction compatible with demyelination: Motor conduction velocity (MCV) < 75% of the lower limit of normal; DML or shortest F wave latency 130% of the upper limit of normal or absence of F waves all after 16 – 20 stimuli. CMAP amplitude on distal stimulation of at least 0·5 mV
4. Normal sensory-nerve conduction in arm segments with motor conduction block. Normal sensory nerve action potential (SNAP) amplitudes on distal stimulation.

Definite MMN: 1 – 11 on clinical criteria, 1 on laboratory criteria, and 1 and 4 on electrodiagnostic criteria

Probable MMN: 1 – 3 and 6 – 11 on clinical criteria, 1 on laboratory criteria, and 2 and 4 on electrodiagnostic criteria

Possible MMN: 1 and 7 – 11 on clinical criteria, 2 or 3 on laboratory criteria, and 3 and 4 on electrodiagnostic criteria

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2013 Forward     

02/01/2024	Annual review, no change to policy intent.
01/25/2024	Change policy category to Prescription Drug. No other changes made.
11/14/2023	Interim review, adding code J1576 to coding section effective 7/1/2023. No other changes made.
02/15/2023	Annual review, no change to policy intent.
07/14/2022	Interim review to add medical necessity statement:  • Patient with dermatomysitis or polymyositis that is refractoory to treatment with corticosteroids; in combination with other immunosuppressive agents.
02/15/2022	Annual review, no change to policy intent.
03/15/2021	Adding code J1554 to coding section. No other changes made.
02/17/2021	Annual review, no change to policy intent.
06/17/2020	Updated coding. Added Code J1558 to be effective 7/1/2020. No other changes.
02/24/2020	Annual review, updating policy criteria for specificity of requirements. Also updating description, rationale and references.
02/25/2019	Annual review, no change to policy intent. Updating rationale, references and coding.
09/12/2018	Interim review adding: GamaSTAN (human immune globulin) may be considered medically necessary for hepatitis A virus prophylaxis or for the prevention or modification of measles in susceptible individuals when the following criteria are met
05/03/2018	Annual review, updating background, description, rationale, references and coding. Policy verbiage updated to indicate changes in neuromyelitis optica: "steroids or plasma exchange" changed to "first-line treatment" since plasma exchange is considered investigational for this condition.
11/28/2017	Updating with 2018 coding. No other changes.
02/21/2017	Annual review, policy verbiage updated to include: The following were changed from medically necessary to investigational: treatment of antibody mediated rejection following solid organ transplantation, patients with neonatal sepsis (prophylaxis or treatment), patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. The following were changed from investigational to medically necessary: polymyositis, Wegener granulomatosis and stiff person syndrome. The following were new indications added as medically necessary for patients with chronic lymphocytic leukemia who have IgG levels <400 mg/dL and persistent bacterial infections, patients with neuromyelitis optica as an alternative for patients with contraindication or lack of response to steroids or plasma exchange particularly in children. The following were new indications added as investigational for patients with acute myocarditis and patients with refractory recurrent pericarditis. Also updating background, description, regulatory status, guidelines, rationale and references.
03/14/2016	Interim review to update guidelines. No other changes being made.
02/23/2016	Annual review, hemolytic disease of the fetus an dnewborn added to the medically necessary statement and postpolio syndrome added to the investigational statement. Updating background, description, policy, rationale and references.
11/23/2015	Interim review to add J1556 to code list.
02/17/2015	Annual review, updated rationale, references and guidelines. Added polyradiculopathy as medically necessary.Added coding.
1/23/2013	NEW POLICY