| Coverage Policy Manual | |
| Policy #: | 2024064 |
| Category: | Pharmacy |
| Initiated: | January 2025 |
| Last Review: | September 2025 |
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| Immune Globulin, Autoimmune, Rheumatic and Neurologic Indications | |
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| Description: |
Human immune globulin replacement therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral antigens. Three formulations of human IgG are available for delivery by intravenous infusion (IVIG), by subcutaneous infusion (SCIG), or by intramuscular (IMIG) depot injections.
IVIg is an antibody-containing solution obtained from the pooled plasma of healthy blood donors that contains antibodies to greater than 10 million antigens. IVIG has been used to correct immune deficiencies in individuals with either inherited or acquired immunodeficiencies and has also been investigated as an immunomodulator in diseases thought to have an autoimmune basis. Several IVIG products are available for clinical use in the U.S.
Subcutaneous infusion immune globulin is used for treating individuals with primary immunodeficiencies (PID). A genetic basis for over 80 different types of PID has been discovered, the most common being primary antibody deficiency (PAD) associated with low levels or total lack of normal circulating immunoglobulins.
Regulatory Status
The following IVIG products have been approved by the FDA: Carimune (ZLB Bioplasma, Flebogamma (Grifols), Gammagard (Baxter), Gamunex-C (Grifols), Gammaked (Kedrion Biopharma), Octagam (Octapharma), Polygam S/D (Baxter), Privigen (CSL Behring), Bivigam (Biotest Pharmaceuticals), Nanogam (Prothya Biosolutions), Panzyga (Pfizer), Alyglo (GC Biopharma) and Asceniv (ADMA Biologics).
At least one immune globulin product is FDA-approved to treat the following conditions:
The following SCIG products are FDA approved: Gamunex-C (Grifols), and Gammaked (Kedrion Biopharma, Cambridge, MA), Hizentra (CSL Behring), HyQvia (Takeda Pharmaceuticals), Cuvitru (Takeda Pharmaceuticals), Cutaquig (Pfizer) and Xembify (Grifols Therapeutics).
The following IGIM products have been approved by FDA: GamaSTAN (Grifols Therapeutics).
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
After December 31, 2024, please refer policy number 1997113 for primary and secondary immunodeficiency indications and policy number 2024065 for hematologic, transplant, infectious disease and miscellaneous indications.
For members of plans that utilize an oncology benefits management program, Prior Authorization is required for this service and is managed through the oncology benefits management program for oncology-related indications.
For contracts subject to Arkansas Act 1054/Act 876 OFF-LABEL USE OF DRUG TREATMENTS TO TREAT INDIVIDUALS DIAGNOSED WITH PEDIATRIC ACUTE- ONSET NEUROPSYCHIATRIC SYNDROME AND PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS ASSOCIATED WITH STREPTOCOCCAL INFECTION [individual, blanket, or any group plan, policy, or contract for healthcare services issued, renewed, or extended in this state by a healthcare insurer, health maintenance organization, hospital medical service corporation, or self-insured governmental or church plan in this state (all fully-insured and state government such as ASE/PSE, ASP)] shall provide coverage for off-label use of intravenous immunoglobulin, also known as "IVIG", to treat individuals diagnosed with pediatric acute-onset neuropsychiatric syndrome or pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, or both, on or after January 1, 2022, under a an individual-specific treatment plan established by the Childhood Post-infectious Autoimmune Encephalopathy Clinic established by the University of Arkansas for Medical Sciences in collaboration with Arkansas Children's Hospital. Effective April 13, 2023, this benefit NO LONGER REQUIRES prior authorization.
This policy applies to outpatient treatment only.
For contracts not subject to Arkansas Act 1054/Act 876, the use of IVIG in the treatment of PANDAS/PANS is NOT COVERED.
INITIAL AND CONTINUATION APPROVAL will be for duration of treatment course or 12 months (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.
Effective September 2025
Select IVIG products are preferred.
Preferred IVIG Products:
HCPCS Brand Name
J1459 Privigen
J1556 Bivigam
J1557 Gammaplex
J1561 Gammaked, Gamunex-C
J1566 Gammagard S/D, Carimune NF
J1568 Octagam
J1569 Gammagard
J1572 Flebogamma
J1599 Panzyga
J1552 Alyglo
Non-preferred IVIG Products:
HCPCS Brand Name
J1554 Asceniv
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Immune globulin meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when
ALL the following criteria are met:
All requests for intravenous immunoglobulin require documentation of actual body weight and height information for dose calculation. Dosing should be calculated on adjusted body weight in individuals with BMI higher than 30 or actual body weight equal or greater than 120% of ideal body weight (see policy guidelines).
Requests for coverage of off-label conditions not listed in the covered section should be submitted for review and include references from peer reviewed journals which support coverage for the proposed condition.
INITIAL APPROVAL:
NEUROLOGIC CONDITIONS
Individual is using for treatment of one of the following neurologic conditions:
RHEUMATIC DISORDERS
Individual is using for treatment of one of the following rheumatic disorders:
AUTOIMMUNE CONDITIONS
Individual is using for treatment of one of the following autoimmune conditions:
CONTINUATION OF THERAPY:
Individual is using for treatment of one of the following conditions, has met indication specific initial criteria, and has demonstrated clinically significant improvements
OR demonstrates continued need (i.e., individual has had a positive response or stabilization at current dose, worsening of symptoms from a dose decrease or increase in dosing interval, or has experienced a relapse from a previous discontinuation). For FDA labeled indications, immune globulin must be dosed in accordance with FDA label unless otherwise specified:
Individual is using for treatment of one of the following conditions and meets the following criteria:
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
Immune globulin for any indication or circumstance not described above or in a related policy as covered, including but not limited to the following, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
For members without contracts without primary coverage criteria or in a related policy as covered, Immune globulin, for any indication or circumstance not described above, including but not limited to the following, is considered
investigational:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
POLICY GUIDELINES
Adjusted body weight guidelines:
Dosing should be calculated using adjusted body weight if one or more of the following criteria are met:
Dosage of immunoglobulins is highly variable depending on individual response, indication or product selected. Refer to prescribing literature (e.g., package insert). This information is not meant to replace clinical decision making when initiating or modifying medication therapy and should only be used as a guide. Individual-specific variables should be considered.
Impaired antibody response to vaccination is defined as:
Examples of electrodiagnostic study findings consistent with CIDP:
Laboratory antibody level guidelines:
Deficiency levels include values
less than the lower limit of normal based on the reference range provided in the policy guidelines or more than two standard deviations
below the mean level for age-matched healthy individuals.
IgG subclass lower limits of normal (Mlabs, 2017):
Test/Age IgG Subclass Reference Ranges (mg/dL)
IGG1
0 – less than 1 year 180 - 770
1 – less than 2 years 250 - 770
2 – less than 6 years 320 - 950
6 – less than 12 years 360 - 1080
12 – less than 16 Years 340 - 1100
Greater than 16 years 340 - 1000
IGG2
0 – less than 1 year 25 - 240
1 – less than 3 years 30 - 300
3 – less than 6 years 50 - 340
6 – less than 12 years 60 - 420
12 – less than 16 Years 70 - 500
Greater than 16 years 100 - 540
IGG3
0 – less than 1 year 20 - 85
1 – less than 3 years 15 - 80
3 – less than 12 years 10 - 120
12 – less than 16 Years 20 - 150
Greater than 16 years 20 - 170
IGG4
0 – less than 1 year 0 - 60
1 – less than 3 years 0 - 80
3 – less than 6 years 2 - 110
6 – less than12 years 2 - 120
12 – less than 16 Years 4 - 125
Greater than 16 years 6 – 130
**Immunoglobulin Reference Range (Mlabs Immunoglobulin, 2023):
Test/Age Reference Range (mg/dL)
IMMUNOGLOBULIN A
Cord blood (age less than 1 month) 1 - 4
1 month 2 - 50
2-9 months 4 - 80
10-11 month 15 - 90
1-4 years 15 - 160
5-11 years 35 - 250
12-150 years 40 - 350
IMMUNOGLOBULIN G
Cord blood (age less than 1 month) 610 - 1540
1 month 240 - 870
2-5 months 170 - 670
6-9 months 210 - 870
10-11 months 280 - 1030
1 year 330 - 1160
2-3 years 405 - 1160
4-5 years 440 - 1190
6-150 years 620 - 1520
IMMUNOGLOBULIN M
Cord blood (age less than 1 month) 6 - 25
1 month 20 - 80
2-5 months 25 - 95
6-11 months 35 - 140
1-7 years 40 - 190
8-11 years 50 - 240
12-150 years 50 - 370
Myasthenia Gravis Foundation of America (MGFA) Clinical Classification:
DOSAGE AND ADMINISTRATION
For FDA labeled indications, Immune globulin must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication below.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
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| Rationale: |
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
Due to the pharmacokinetic qualities of intravenous immunoglobulin, namely the small volume of distribution of this drug, the precision-dosing strategy has been adopted by numerous healthcare providers and facilities. Peer-reviewed, published evidence such as study conducted by Dr. Stump et al in patients with hematologic malignancies has found that no differences in 30-day infection rate or 60-day infection rate between precision (dose based on adjIBW for obese individuals or IBW for non-obese individuals) and traditional (weight-based with no adjustment) dosing strategies were identified. In obese patients with primary immunodeficiency state of common variable immunodeficiency disorder (CVID), a peer-reviewed published article by Dr. Ameratunga has supported the precision dosing of IVIG, stating that “most experts recommend this initial SCIG/IVIG dose should be based on adjusted body weight (AjBW) rather than actual body weight. The basis for this recommendation has been that administered immunoglobulin does not distribute to body fat and is only present in the intravascular space and extracellular fluids. The use of adjusted body weight, rather than ideal body weight (IBW) or lean body weight (LBW) is based on the presumption that extracellular fluid is increased in patients with increased adipose tissue (also described by Rocchio et al (Rocchio MA, Hussey AP, Southard RA, Szumita PM. Impact of ideal body weight dosing for all inpatient i.v. immune globulin indications. Am J Health Syst Pharm. 2013;70(9):751–752). Among institutions who currently use precision-dosing for IVIG are Children’s Hospital of Philadelphia, Stanford Healthcare System, Health and Community Department of Canada, University of Maryland Medical Center and UConn Health.
Given the heterogeneous nature and relapsing-remitting course of many of the diseases for which IVIg has been investigated as therapy, randomized, controlled trials (RCTs) are important for evaluating true benefit. However, in the case of rare disease, RCTs may be neither likely nor feasible. In these cases, reports of series data from at least 10 patients and consistent trends in results may support conclusions. Aside from the labeled indications, the use of IVIg has been investigated in a variety of diseases as follows:
ACQUIRED FACTOR VIII DEFICIENCY/ACQUIRED HEMOPHILIA
Acquired factor VIII deficiency/Acquired hemophilia is a coagulopathy caused by the development of autoantibodies directed against specific domains of the coagulation Factor VIII molecule. Factor VIII becomes bound in the coagulation cascade which results in bleeding. Mortality rates as high as 21% have been reported. There are no randomized trials, and standard therapy, based on a randomized trial has been corticosteroids and cyclophosphamide (Green, 1993). Cyclosporine has been substituted because of side of effects of long-term corticosteroid + cyclophosphamide. Treatment with IVIg has been reported in case series (Bossi, 1998), but a meta-analysis of 245 patients with acquired Factor VIII hemophilia found that IVIG had a poor complete response rate (Delgado, 2003). A protocol consisting of antibody depletion through immunoadsorption, IVIG, immunosuppression, and high dose factor VIII supplementation, reported in 2005, described 35 patients with an 88% long-term response rate (93% if 5 patients with malignancy were excluded) (Modified Bonn-Malmö Protocol) (Zeitler, 2005). Neither the AHFS nor the Clinical Pharmacology Online drug compendia recommend IVIG for treatment of acquired hemophilia. The Canadian Expert Panel on IVIG for hematological uses and the Academy of Allergy and Immunology Expert Panel on IVIG recommend IVIG for treatment of acquired hemophilia if standard therapy has failed.
ADRENOLEUKODYSTROPHY
X-linked adrenoleukodystrophy is an inborn error of peroxisomal metabolism characterized by progressive demyelination of the CNS and by hypoadrenalism. There is very little information on the use of IVIG for adrenoleukodystrophy, and those results are conflicting (Mike, 1989; Cappa, 1994). The Canadian IVIG Hematology & Neurology Expert Panel (Robinson, 2007) and the American Academy of Allergy, Asthma, and Immunology (Orange, 2006) recommend against the use of IVIG in adrenoleukodystrophy.
ALZHEIMER’S DISEASE
Antibodies against beta-amyloid have been found in human immunoglobulin preparations, leading to potential use of IVIG as treatment of Alzheimer’s disease. A claims based retrospective review of IVIg for Alzheimer’s disease was published in 2009 (Fillit H) showed that previous treatment with IVIG was associated with a reduced risk of development of Alzheimer’s and related disorders in patients greater than or equal to 65 years of age. No review articles recommend IVIG treatment of Alzheimer’s disease. Use of IVIG for Alzheimer’s disease is being studied in clinical trials to determine safety and effectiveness (NCT00818662, NCT00299988, NCT00812565).
AMYOTROPHIC LATERAL SCLEROSIS
Small prospective case series showed no benefit of IVIG for treatment of ALS (Dalakas, 1994; Meucci, 1996). The Canadian IVIG Hematology & Neurology Expert Panel (Robinson, 2007) and the American Academy of Allergy, Asthma, and Immunology (Orange, 2006) recommend against the use of IVIG in adrenoleukodystrophy.
APLASTIC ANEMIA
There have been no clinical trials on IVIG for aplastic anemia. Rare case reports (Sadowitz, 1990; Chen, 1995) and letters to the editor (Bodenstein, 1991) have described benefit, but other studies have shown no benefit (Miceli, 1990; Sumimoto, 1992; Bejaoui, 1993). The Canadian IVIG Hematology & Neurology Expert Panel (Robinson, 2007) recommends against IVIG for aplastic anemia. Neither the AHFS nor Clinical Pharmacology Online drug compendia recommend use of IVIG in aplastic anemia.
ASTHMA
There have been 3 double-blind, placebo-controlled studies of IVIG in asthma (Niggemann, 1998;). Two of the 3 showed no significant improvement (Kishiyama, 1999; Salum, 1999), and the third reported significant steroid-sparing effect in a subgroup that required relatively high daily doses of oral steroids. The American Academy of Allergy and Immunology expert panel recommends against the use of IVIG for asthma (Orange, 2006). Neither the AHFS nor the Clinical Pharmacology Online compendia recommend IVIG for asthma.
AUTISM
There are no clinical trials reported on the use of IVIG to treat the neurological effects of autism, nor are there any ongoing trials of IVIG for autism listed on clinicaltrial.gov. (Oct 2010). A randomized controlled trial of IVIG given orally for treatment of gastrointestinal symptoms of associated with autism has been reported. This trial (NCT00110708) found no benefit (Handen, 2009). An uncontrolled, unblinded study of 10 autistic children who received IVIG showed benefit in one child (Plioplys, 1998). A brief report of a pilot trial described no benefit (DelGiudice-Asch, 1999). The American Academy of Allergy, Asthma & Immunology expert panel (Orange, 2006), and the Canadian IVIG Hematology & Neurology Expert Panel (Robinson, 2007) recommend against IVIG for autism.
AUTOIMMUNE BLISTERING DISEASES, INCLUDING PEMPHIGUS
Corticosteroids and immunosuppressive agents are considered first line therapy. IVIG therapy is the preferred therapy for patients who are resistant, nonresponsive, have contraindications, or develop serious catastrophic adverse effects (Ahmed, 2003). No clinical trials have been reported for IVIG for pemphigus or other autoimmune blistering diseases. Two randomized controlled trials are listed on clinicaltrial.gov. NCT00483119 is an ongoing FDA sponsored trial at NYU Medical Center, initiated in 2007 with estimated completion date of 2011, comparing IVIG versus IVIG plus cyclophosphamide in patients with pemphigus that are not responding to, or have developed complications from, standard therapy. A second study, in Japan (NCT00809822) recently completed but unreported, is a randomized, placebo controlled trial of IVIG for patients with bullous pemphigoid unresponsive to corticosteroids. Prospective, non-randomized. open label clinical studies on patients who are unresponsive to corticosteroids and immunosuppressive agents have shown response to IVIG (Toth, 1999; Engineer, 2000; Ahmed, 2001; Sami, 2002; Bystryn, 2002; Baum, 2002; Ahmed, 2002). IVIG has not been compared to newer biologics (e.g., anti-tumor necrosis alfa drugs).
AUTOIMMUNE ENCEPHALOPATHY
This condition was originally designated in 1966 as “Hashimoto’s encephalopathy”, but more recently has been termed “autoimmune encephalopathy” (Caselli, 2010; Flanagan, 2010). There are few reports of this disease, and treatment has been with glucocorticoids. A few case reports of IVIG for steroid refractory disease have indicated both acute and longer-term benefit from IVIG (Flanagan, 2010; Berger, 2010; Drulovic, 2011). In addition to Hashimoto’s encephalopathy, voltage-gated potassium channel complex antibody-associated encephalopathy (Tan, 2008), and Morvan syndrome (progressive encephaloencephalopathy with rigidity and myoclonus) have been included as autoimmune encephalopathies. IVIG for Hashimoto’s encephalopathy was not been reviewed or commented on by the American Academy of Allergy & Immunology expert panel (2006); the European Federation of Neurological Sciences expert panel (2006); the Canadian expert panel on IVIG for neurological diseases (2007); the Gold, Stangel, and Delakas review of IVIG for neurological diseases (2007); the American Academy of Neurology & Electrodiagnostic Medicine expert panel (2009); or the AHFS or Clinical Pharmacology Online drug compendia (2011). Because of the rarity of this disorder, it is unlikely that prospective trials will be performed. A case series of 72 patients (Flanagan, 2010), reported from the Mayo Clinic showed improvement with glucocorticoids, but relapsed after discontinuation. Some patients responded only to IVIG or received IVIG after failing corticosteroids. Because of the rarity of this disorder, it is unlikely that prospective trials will be performed.
AUTOIMMUNE URTICARIA (ANGIOEDEMA)
There are rare case reports and two case series (Pereira, 2007; Mitzel-Kaoukhov, 2010) which describe IVIG treatment for autoimmune urticaria. Neither the AHFS nor the Clinical Pharmacology Online drug compendia recommend IVIG for treatment of autoimmune urticaria. No major medical group recommends IVIG for autoimmune angioedema. The American Academy of Allergy & Immunology expert panel states, “Because there is not clear evidence that the use of IVIG benefits patients with chronic urticaria, additional studies are needed” (Orange, 2006).
CARDIOMYOPATHY, DILATED CARDIOMYOPATHY
The Intervention in Myocarditis and Acute Cardiomyopathy trial, a multi-center, placebo-controlled trial to determine whether IVIG improves left ventricular ejection fraction in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis was reported in 2001 (McNamara, 2001). This trial was done because of reports from uncontrolled studies which purported to show benefit. The study failed to demonstrate evidence of therapeutic efficacy.
CHRONIC FATIGUE SYNDROME
A randomized, double-blind, placebo-controlled trial of 3 different doses of IVIG in 99 adult patients with chronic fatigue syndrome was reported in 1999 (Volmer-Conna, 1997). Outcome was assessed by changes in a series of self-reported measures (quality of life, standardized diaries of daily activities, profile of mood states, and Karnofsky performance scale). No dose of IVIG was associated with a specific therapeutic benefit. The American Academy of Allergy and Immunology recommends against the use of IVIG for chronic fatigue syndrome (Orange, 2008).
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
A double-blind placebo-controlled study comparing IVIg to placebo in patients with progressive or relapsing CIDP reported a significant effect of IVIg in 63% of patients compared to no effect in the placebo group. A randomized single-blinded study comparing IVIg to plasma exchange reported equivalent beneficial outcomes for both therapies. Open-label treatment of 26 patients with type 2 diabetes and meeting electrophysiologic criteria for CIDP showed significant improvement in 21, suggesting benefit in diabetic CIDP as well. A possible advantage to IVIg treatment is the ability to administer the drug in the home.
A multicenter randomized, placebo-controlled trial with a 10% caprylate-chromatography purified intravenous immune globulin product given every 3 weeks for up to 24 weeks showed improvement in inflammatory neuropathy cause and treatment criteria (INCAT) in 54% of treated patients compared to 21% of placebo that was maintained through 24 week 24. During an extension period of the trial, participants who continued to receive IVIG-C had a longer time to relapse than did patients treated with placebo (Hughes, 2008).
CLOSTRIDIUM DIFFICILE ENTEROCOLITIS
IVIG has been reported in single case reports and small case series to be beneficial for treatment of patients with enterocolitis unresponsive to vancomycin and metronidazole (Leung, 1991; Salcedo, 1997; McPherson, 2006; Murphy, 2006), and has been ineffective in other studies (Leung, 2007). The American Academy of Allergy & Immunology expert panel concluded that IVIG “might be beneficial” (Orange 2006). The Medical Letter recommends IVIG for treatment of frequent relapse of C. difficile enterocolitis, based on the McPherson paper (Med Letter Drugs Ther, 2006a). A 2008 review concluded, “Despite multiple case reports of successful treatment with IVIG, good sound clinical trials are lacking and thus make it difficult to recommend this for treatment of CDI at this time (Hedge, 2008).
DERMATOMYOSITIS
A randomized controlled trial comparing IVIg to placebo in 15 patients with refractory dermatomyositis reported significant increases in muscle strength in the IVIg group. Repeated transfusions every 6 to 8 weeks may be required to maintain a benefit. (Delakas, 1993) In 2 case series of 18 and 19 patients, a significant number of patients had reduction in corticosteroid use or were otherwise considered responders. In a non-randomized comparison of prednisone plus cyclosporine A, with or without IVIg, patients (12 with DM, 8 with PM) given IVIg had a higher probability of remission. Thus, the available data suggest benefit in DM, but are insufficient for firm conclusions. A recent patient series of IVIg in patients with refractory PM showed significant clinical improvement in more than two-thirds of patients. IVIG for treatment of refractory dermatomyositis is recommended by the AHFS and Clinical Pharmacology Online drug compendia, and by multiple expert panels.
DIABETES MELLITUS, AUTOIMMUNE
A major cause of type I diabetes mellitus is considered to be autoimmune disease which destroys the insulin producing islet cells of the pancreas. IVIG was studied in a randomized, placebo-controlled trial and found to have no benefit (Colagiuri, 1996). The American Diabetes Association does not recommend IVIG to treat type I or type II diabetes mellitus. Neither the AHFS nor the Clinical Pharmacology Online drug compendia recommend IVIG to treat autoimmune diabetes mellitus.
DIABETIC AMYOTROPHY
There are a few case reports of IVIG for amyotrophy, but no trials have been reported. Monotherapy with IVIG was given to a total of 17 patients from 3 studies; all were considered to have improved. (Krendel, 1995; Pascoe, 1997; Jaradeh, 1999). A randomized controlled trial (NCT00004407) was scheduled by the Mayo Clinic, but has not recruited participants. The Canadian IVIG Hematology & Neurology Expert Panels recommends against the use of IVIG in diabetic polyneuropathy, mononeuropathy, or proximal lower limb neuropathy (Robinson, 2007). A 2009 Cochrane review of immunotherapy for diabetic amyotrophy (Chan, 2009) concluded, “there is presently no evidence from randomized trials to support any recommendation on the use of any immunotherapy treatment in diabetic amyotrophy.”
DI GEORGE SYNDROME
Di George syndrome is primarily a congenital T-cell deficiency associated with defective development of organs dependent on cells of embryonic neural crest origin, and includes congenital cardiac defects, failure of parathyroid development, and absence of the thymus. Facial abnormalities also may occur. Serum immunoglobulin concentrations are frequently normal, but impaired antibody responses to polysaccharide and other antigens have been found in approximately one third of patients with Di George syndrome, but they seldom warrant IgG administration (Kobrynski, 2006).
ENCEPHALITIS, ACUTE, DISSEMINATED
Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the CNS, commonly preceded by an infection, and predominately affects the white matter of the brain and spinal cord. It occurs predominately in pediatric patients, but can occur in adults. It is classically described as monophasic, but can be recurrent and multiphasic, with wide variation of severity. There is no standard therapy; most treatment approaches have employed some form of nonspecific immunosuppressant therapy including steroids, IVIG (Kleiman, 1995, Nishikawa, 1999; Sahlas, 2000; Marchioni, 2002; Ravaglia, 2006), or plasmapheresis. No randomized controlled trials have been performed, and there have been no studies which have compared IVIG with steroids, plasmapheresis, or other immunomodulatory treatments. The American Academy of Allergy & Immunology (Orange, 2006), the International Pediatric MS Study Group (Tenembaum, 2007), and the Canadian IVIG Hematology & Neurology Expert Panels (Robinson, 2007) recommend IVIG if corticosteroids are ineffective.
FISHER SYNDROME
Fisher syndrome is a rare, acute neurological disorder characterized by a triad of clinical manifestations that includes brain-damage associated abnormal coordination (ataxia), a condition that involves the paralysis of the eyes called ophthalmoplegia, and a generalized absence of reflexes (areflexia). A Cochrane Neuromuscular Review in 2007 identified no randomized prospective controlled trials of immunotherapy in Fisher syndrome (Overall JR, 2007). Several case reports and case series have been published on the treatment of Fisher syndrome with IVIG, and patients who received IVIG experienced clinical recovery in a slightly shorter time frame than would be expected based on the natural history of the disease (Arakawa, 1993; Zitko, 1994; Benito-Leon, 1996; Bushra, 2000; Kaushik, 2005; Mori, 2007). Neither AHFS nor Clinical Pharmacology Online recommends IVIG for Fisher’s syndrome. The AANEM states, “On the basis of the single retrospective analysis and case reports, it is difficult to clearly define the role of VIG in treating Fisher syndrome. The literature suggests that best medical management may suffice for many patients (Donofrio, 2009).
GOOD SYNDROME (Durable Hypogammaglobulinemia Associated with Thymoma)
Good syndrome is characterized by hypogammaglobulinemia and acquired immunodeficiency associated with benign or malignant thymoma (Good, 1954). Autoimmunity to to B lymphocyte lineage causes severe deficiency in B lymphocytes and hypogammaglobulinemia, resulting in acquired immunodeficiency vulnerable especially to bacterial infection (Kelleher, 2003). Hypogammaglobulinemia and susceptibility to infection may persist for several years after resection of the thymoma (Tarr, 2001; Kitamura, 2009). IVIG replacement is recommended by the International Union of Immunological Societies (IUIS Scientific Committee, 1999)
GUILLAIN_BARRE SYNDROME
Two randomized studies comparing IVIg with plasma exchange reported equivalent outcomes for the two treatment approaches. In addition, one study has reported that there is no health benefit in combining plasma exchange with IVIg. Therefore, choice of therapy may be dictated by practical concerns, i.e., access to plasma exchange and need for hospitalization.
HEMOLYTIC DISEASE OF NEWBORN WITH JAUNDICE (ISO-IMMUNE HEMOLYTIC DISEASE OF NEWBORN)
A Cochrane review of 3 randomized controlled trials totaling 189 infants with rhesus and ABO incompatibility concluded, “Although the results show a significant reduction in the need for exchange transfusion in those treated with IVIG, the applicability of the results is limited. The number of studies and infants included is small and none of the 3 included studies was of high quality…Further well designed studies are needed before routine use of IVIG can be recommended for the treatment of iso immune hemolytic jaundice (Alcock, 2002). This review was updated in 2009 with a similar conclusion: “The role of IVIG remains uncertain, particularly in hospitals that do not use early rate of rise of bilirubin as an indicator for exchange transfusion. Since it appears safe, it may have a role in special circumstances such as parental refusal for exchange transfusion, or where appropriate blood components for exchange transfusion are unavailable. However, routine use of IVIG for the treatment of iso immune hemolytic jaundice cannot yet be recommended (Alcock, 2009). The American Academy of Allergy and Immunology states, “Multiple anecdotal reports demonstrate benefit from the use of IVIG in autoimmune hemolytic anemia, but the use of IVIG should be considered only when other therapeutic modalities fail. IVIG might decrease the need for exchange transfusion in neonates with iso-immune hemolytic jaundice. However, there are methodologic flaws with these studies, and routine use in this setting is not recommended.” Two randomized controlled trials reported in 2011 found conflicting results: A trial of 80 infants from the Netherlands, which randomly assigned neonates with rhesus hemolytic disease for IVIG or placebo, found no reduction in the need for exchange transfusion or rates of other adverse neonatal outcomes (Smits-Wintjens, 2011). A study from Egypt of 90 infants were randomly assigned to 3 groups: low dose IVIG (0.5gm/kg), high dose IVIG (1g/Kg), and placebo. There was a more rapid decrease in bilirubin, the duration of phototherapy, and hospital stay (Elalfy, 2011).
HYPERIMMUNOGLOBULIN M SYNDROME
Hyper-IgM syndromes are a group of disorders characterized by hypogammaglobulinemia with severely impaired production of specific antibody. Children with hyper-IgM syndrome have decreased levels of IgG and IgA and increased or normal levels of IgM. Although B cells are present, there is an inability to generate specific antibody. As a result, these individuals have recurrent infections similar to those of patients with agammaglobulinemia. Regular replacement therapy with IVIG is crucial for individuals with this disorder, whether it is due to the X-linked or autosomal recessive varieties (Levy, 1997; Winkelstein, 2003; Quartier, 2004). Hyperimmunoglobulin M is also seen in patients with Waldenstrom’s hyperglobulinemia, and rarely in B-cell lymphomas, and may be associated with low immunoglobulin G. The American Academy of Allergy and Immunology (Orange, 2006) recommends IVIG for children with X-linked hyper-IgM syndrome and other autosomal recessive varieties (Orange, 2006).
INCLUSION BODY MYOSITIS
Inclusion body myositis (IBM) is a late onset inflammatory muscle disease (myopathy) with a distinctive pattern of proximal and distal limb atrophy and weakness. In published series it has accounted for between 17 to 30% of all idiopathic inflammatory myopathies but the true proportion may be much higher. In neuromuscular disease referral centers IBM is the commonest acquired myopathy over the age of 50 years. Muscle biopsy is essential for diagnosis and can be pathognomonic. It usually shows varying degrees of inflammation, with muscle fibers containing rimmed vacuoles but also additional features which include the presence of nuclear and cytoplasmic inclusions and the abnormal deposition of proteins such as amyloid, ubiquitin and phosphorylated tau. There are agreed criteria for the diagnosis of IBM utilizing clinical, laboratory and biopsy findings. In the majority of cases IBM is a sporadic and isolated disorder. However, there are a few cases where IBM occurs in association with an autoimmune disease. In rare instances familial cases of IBM have occurred but as these are usually not associated with inflammation, they are called hereditary inclusion body myopathies (h-IBM). They are a heterogenous group of disorders characterized clinically by progressive muscular weakness and atrophy beginning in the hands or feet. So far, five different hereditary forms (1 autosomal recessive, 4 autosomal dominant) have been characterized. Dalakas and colleagues have reported on a double-blind, placebo-controlled crossover study comparing IVIg to placebo in 19 patients with inclusion body myositis (Delakas, 1997). There was no statistically significant improvement in overall muscle strength in the IVIg group compared to the control placebo group. (Delakas, 2001) reported a RCT of 36 patients with biopsy-proven IBM who received IVIG + prednisone versus placebo + prednisone. IVIG combined with prednisone for a 3-month period was not effective in IBM. A crossover study of 22 patients with sporadic IBM were treated with high-dose IVIG versus placebo (Walter, 2000). Treatment was considered of mild benefit. The European Federation of Neurological Sciences (Skeie, 2006); the American Academy of Allergy & Immunology (Orange, 2006); and the Canadian IVIG Hematology & Neurology Expert Panels (Robinson, 2007) recommend against the use of IVIG for treatment of inclusion body myositis.
IRAK4 IMMUNODEFICIENCY
Four Mendelian primary immunodeficiencies associated with impaired signaling of the Toll Like Receptor (TLR) pathway have been reported, one of which is IRAK4 (Interleukin-1 Receptor Associated Kinase 4). Autosomal recessive IRAK-4 deficiency was first discovered in 2003 (Picard, 2003) and has been described in a less than 100 patients as of 2011. Patients with IRAK-4 deficiency present with invasive and non-invasive pyogenic bacterial infections, but have normal resistance to common fungi, parasites, viruses, and many bacteria. Clinical status and outcome improve with age thought to be due to the development of adaptive antigen-specific T- and B-lymphocyte responses. IVIG is recommended empirically until the patient is at least 10 years old (Picard, 2011). IVIG for IRAK4 immunodeficiency meets coverage criteria based on Expert Opinion, as the number of cases would not allow for appropriate treatment trials, and case studies to date indicate benefit.
KAWASAKI SYNDROME and OTHER VASCULITIDES
Randomized, multicenter studies have shown that high-dose IVIg plus aspirin, given within the first 10 days after the onset of fever, is safe and effective in reducing the prevalence of coronary artery abnormalities in Kawasaki Syndrome.
A RCT of single course IVIg (n=17) vs. placebo (n=17) in patients with persistent active Wegener’s granulomatosis or microscopic polyangiitis associated with anti-neutrophil cytoplasmic antibody found significantly more responders in the IVIg treatment group at 3 months, but no significant differences after 3 months or in the frequency of relapse or use of other medications. Data are inadequate regarding the effectiveness of IVIg in other vasculitides including polyarteritis nodosa and rheumatoid arthritis.
MULTIFOCAL MOTOR NEUROPATHY
In 2010, the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society published guidelines on the management of multifocal motor neuropathy (MMN). The guideline recommends the use of IVIg in the initial and maintenance treatment in patients with MMN (Joint Task Force of the EFNS and the PNS, 2010). Four randomized, controlled, double-blind trials of IVIg for treating MMN (Azulay et al., 1994; Van den Berg et al., 1995; Federico et al., 2000; Le´ ger et al., 2001) have been summarized in a Cochrane systematic review (van Schaik et al., 2005). IVIg treatment was superior to placebo in inducing an improvement in muscle strength in patients with MMN.
MULTIPLE MYELOMA
A review of the current literature shows several review and meta-analysis articles but no reports of trials using IVIG for myeloma patients before or after stem cell transplant.
Blade and Rosifiol (2007) stated the highest risk of infection in myeloma patients is within the first two months of initiation of therapy and in patients with relapsed and refractory disease. The increased susceptibility to infections is multifactorial with the major cause being the impaired antibody production leading to a decrease in uninvolved immunoglobulins. There has been controversy about infection prophylaxis in patients with MM but high-dose immunoglobulins are not recommended.
Raanani (2009) also noted in his meta-analysis that causes for infections in patients who receive HSCT are multifactorial and consist also of causes other than hypogammaglobulinemia. The authors concluded there was no advantage to the use of IVIG in terms of survival or infection prevention.
Other authors have also recommended the limited use of IVIG for myeloma patients: Nucci (2009): consider IVIG if serum IgG level < 500 mg/dL and recurrent serious infection despite prophylactic antibiotics. Ludwig (2007): prophylactic measures such as long-term antibiotic or antiviral medication or use of intravenous immunoglobulins is recommended in patients with repeated infectious complications.
MULTIPLE SCLEROSIS
In terms of its impact on the acute exacerbation rate in patients with relapsing-remitting MS, IVIg is comparable to treatment with beta interferon. Despite a reduction in the acute exacerbation rate, data are inconclusive regarding the impact of IVIg on patients’ disability. There are insufficient data to evaluate the effectiveness of IVIg in treating patients with chronic progressive MS.
A high-quality RCT compared IVIg to placebo in 67 patients, the majority of whom had chronic progressive disease; the trial was terminated early due to lack of benefit either in patients who remained clinically stable or in those with evidence of disease activity. Small series data also suggest no benefit.
In 2002 the American Academy of Neurology published a technology assessment on therapies for multiple sclerosis. This assessment provided a rating of the recommendations, including A (established as effective), B (probably effective, ineffective, or harmful), C (possibly effective, ineffective or harmful) or U (data inadequate). This assessment offered the following recommendation regarding IVIg: The studies of intravenous immunoglobulin (IVIg) to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIg reduces the attack rate in relapsing-remitting multiple sclerosis. (Type C recommendation)
The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression. (Type C recommendation). In contrast, the American Academy of Neurology recommended the use of interferon beta (Type B recommendation) and glatiramer acetate (Type A recommendation). This assessment suggests that IVIg is no longer considered a drug of choice for relapsing-remitting MS, and thus the policy statement in this policy has been revised to indicate that IVIg is not medically necessary. A literature search for the period of 2002 to December 2004 did not identify any additional randomized trials that would prompt reconsideration of the conclusions of the American Academy of Neurology assessment.
MYASTHENIA GRAVIS
One RCT (total n=87) and one retrospective chart review (total n=54) compared IVIg treatment to plasma exchange in acute myasthenic crisis. Myasthenic crisis was defined as an acute episode of respiratory muscle weakness, defined by a forced vital capacity (FVC) of <=1.0 liter or negative inspiratory force of <= 20 cm H20, or requirement of mechanical ventilation. One crossover study compared these therapies in 12 patients with moderate-to-severe disease in a stable phase. Results for all 3 trials showed that IVIg and plasma exchange had similar efficacy over time, although improvement may be more rapid with plasma exchange. Series data support benefit with IVIg treatment in patients with acute exacerbations and with refractory disease or who are unable to tolerate standard treatment. One series of 10 children with refractory disease suggests short-term benefit with IVIg but limited long-term benefit. Refractory myasthenia gravis has been defined as those patients with persistent symptoms despite immunosuppressive treatment with prednisone and/or azathioprine or those unable to tolerate steroid therapy.
Feasby et al.: Given the limited evidence available, the expert panel agreed IVIG should not be used as maintenance therapy for chronic myasthenia gravis.
Skeie et al.: Trials have not shown evidence of improved functional outcome or steroid-sparing effect with repeated use of IVIG in moderate or severe stable MG (class I evidence).
Multiple resources were reviewed for dosing recommendations for Myasthenia Gravis. In a study by Barth D, et al (2011), 84 patients were randomized with moderate to severe MG defined as a Quantitative Myasthenia Gravis Score for disease severity (QMGS) of >10.5 and worsening weakness to IVIg (Gamunex®, Talecris Biotherapeutics) 1 g/kg/day for 2 consecutive days or PLEX (Caridian Spectra) 1.0 plasma volume exchanges for 5 exchanges. The patients were evaluated at day 14 after treatment for the primary efficacy parameter of change in QMGS and secondary clinical and electrophysiologic parameters and were followed for a total of 60 days. Findings showed that both IVIg and PLEX reduced the QMGS and IVIg was comparable to PLEX in efficacy.
In a Cochrane review, seven RCTs comparing IVIg to no treatment, placebo or PLEX, in people with MG were identified. One trial with 168 people with exacerbations, showed no evidence of superiority of IVIg 2g/kg over IVIg 1 g/kg on the change of MMS after 15 days. (MD 3.84; 95% Cl -0.98 to 8.66).
Cosi V et al, (1991) had 37 patients affected by autoimmune generalized myasthenia gravis (MG) with high‐dose intravenous gammaglobulin (HDIVIg), 400 mg/kg per day on 5 consecutive days. A one‐degree improvement of Oosterhuis global clinical classification of myasthenic severity (OGCCMS), the disappearance of bulbar involvement or both were recorded 12 days after the beginning of the treatment in 70.3% of the patients and persisted up to 60 days in 58.7%. A two‐degree improvement of OGCCMS was recorded in 54.1% of the patients and it was maintained up to 60 days in 37.8%. The percentage of improvement did not significantly differ between patients entering the treatment in a long‐standing, drug‐refractory stationary phase of the illness (n = 26) and patients who received HDIVIg in an acute phase of MG (n = 11).
MYD88 GENE DEFICIENCY
Four Mendelian primary immunodeficiencies associated with impaired signaling of the Toll Like Receptor (TLR) pathway have been reported, one of which is autosomal recessive MyD88 deficiency which was first discovered in 2008. (von Bernuth, 2008). Deficiency in the MYD88 gene results in invasive pyogenic infections. IVIG is not recommended for patients with MYD88 gene deficiency by any review group, and is not recommended in the review of this deficiency by Picard, et al (Picard, 2011).
NEONATAL SEPSIS
A 2010 Cochrane review found no benefit, but recommended waiting on the International Neonatal Immunotherapy Study results before a definitive conclusion was reached. The INIS Collaborative Group randomized controlled trial was reported in September 2011 (Brocklehurst, 2011) and found no benefit of IVIG in infants with neonatal sepsis.
PARANEOPLASTIC RETINOPATHY (CANCER ASSOCIATED RETINOPATHY, MELANOMA ASSOCIATED RETINOPATHY, AUTOIMMUNE RETINOPATHY ASSOCIATED WITH NEOPLASM) Paraneoplastic vision loss is characterized by sudden, progressive loss of vision associated with photosensitivity, ring scotomata, visual field defects, and abnormal electroretinogram believed to be caused by an autoimmune effect on the retina or optic nerve from anti-retinal autoantibodies associated with a remote cancer (Jacobson, 1990; Guy, 1999; Katsuta, 2002). Autoantibodies (anti-recoverin, anti-enolase, anti-carbonic anhydrase II, and anti-transducin) affect both rod and/or cone function, causing rapid visual loss (Murphy, 1997; Adamus, 2004; Dot, 2005; Weleber, 2005; Adamus, 2009). No clinical trials have been published on the use of IVIG for treatment of paraneoplastic vision loss, cancer associated retinopathy, or melanoma associated retinopathy. No published paper from any IVIG expert panel has reviewed IVIG for treatment of paraneoplastic vision loss. A few case reports suggest improvement following IVIG for paraneoplastic vision loss (Guy,1999; Keltner, 2001; Subhadra, 2008), and reduction in anti-enolase antibody has been described following IVIG (Adamus (2004). Neither AHFS nor Clinical Pharmacology Online drug compendia recommend IVIG for treatment of paraneoplastic retinopathy. IVIG for paraneoplastic retinopathy is considered to meet Primary Coverage Criteria because 1) of the critical nature of this disorder; 2) of the lack of other appropriate therapeutic measures; 3) it is unlikely that prospective trials will be performed due to the rarity of this condition; and 4) there are published case series indicating benefit.
PARANEOPLASTIC SYNDROME (EATON-LAMBERT DISEASE)
Results of a double-blind, placebo-controlled, crossover, randomized study of IVIg versus placebo in 11 patients with paraproteinemic IgM demyelinating polyneuropathy showed only a mild and transitory effect in 3 patients. There are inadequate data on the use of IVIg in paraneoplastic syndromes, such as Eaton-Lambert disease.
PEMPHIGUS AND OTHER AUTOIMMUNE BLISTERING DISEASES
Corticosteroids and immunosuppressive agents are considered first line therapy. IVIG has been shown to decrease circulating autoantibodies in pemphigus, and addition of immunosuppressive drugs to IVIG has an additive effect. Based on uncontrolled studies (Ahmed, 2003), IVIG therapy is the preferred therapy for patients who are resistant, nonresponsive, have contraindications, or develop serious catastrophic adverse effects. No clinical trials have been reported for IVIG for pemphigus or other autoimmune blistering diseases. Two randomized controlled trials are listed on clinicaltrial.gov. NCT00483119 is an ongoing FDA sponsored trial at NYU Medical Center, initiated in 2007 with estimated completion date of 2011, comparing IVIG versus IVIG plus cyclophosphamide in patients with pemphigus that are not responding to, or have developed complications from, standard therapy. A second study, in Japan (NCT00809822) recently completed but unreported, is a randomized, placebo controlled trial of IVIG for patients with bullous pemphigoid unresponsive to corticosteroids. Prospective, non-randomized, open label clinical studies on patients who are unresponsive to corticosteroids and immunosuppressive agents have shown response to IVIG (Toth, 1999; Engineer, 2000; Ahmed, 2001; Sami, 2002; Bystryn, 2002; Ahmed, 2002; Baum, 2006). IVIG has not been compared to newer biologics (e.g., anti-tumor necrosis alfa drugs).
POST TRANSPLANT HYPOGAMMAGLOBULINEMIA
Hypogammaglobulinemia has been identified following lung (Kawut, 2005; Yip, 2006; Robertson, 2009), heart (Corales, 2000), AND kidney (Boddana, 2011) transplantation. There has been consideration that this may be due to the use of mycophenolate mofetil to prevent allograft rejection, and this drug is known to be associated with an increased risk of bacterial infection.
POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
PDLDs are a heterogenous group of abnormal lymphoid proliferations that occur after solid organ transplant or hematopoietic transplantation. PTLDs range from hyperplasia to aggressive lymphomas with 60-70% being Epstein-Barr virus positive.
PREVENT RECURRENT PREGNANCY LOSS IN UNSELECTED POPULATION
A Cochrane review on Immunotherapy for recurrent miscarriage published initially in 2006, and edited in 2010, looked at 20 trials on various forms of immunotherapy, including 7 with IVIG, for treatment of recurrent abortion. They concluded that IVIG provided no significant beneficial effect over placebo in approving live birth rate (Porter, 2010). Another systematic review of eight trials (Hutton, 2007) involving 442 women found that IVIG did not significantly increase the odds ratio of live birth when compared with placebo for treatment of primary recurrent miscarriage (primary - miscarriage occurring in women with no recognized cause, e.g., antiphospholipid syndrome).
PREVENT RECURRENT PREGNANCY LOSS IN ANTIPHOSPHOLIPID SYNDROME
The Pregnancy Loss Study Group multicenter, placebo-controlled pilot study of IVIG treatment of antiphospholipid syndrome during pregnancy compared treatment with heparin and low-dose aspirin plus IVIG with heparin and low-dose aspirin plus placebo in a group of 16 women who met strict criteria for antiphospholipid syndrome in 16 women (Branch, 2000). Obstetrical outcomes were excellent in both groups, with all women being delivered of live-born infants after 32 weeks gestation. A second randomized controlled trial of 40 women with recurrent abortion (at least 3 occurrences) and repeatedly positive test results for anticardiolipin or lupus anticoagulant were randomized to receive IVIG or low molecular weight heparin plus low dose aspirin (Triolo, 2004). The women treated with low molecular weight heparin plus low-dose aspirin had a higher rate of live births (84%) than those treated with IVIG (57%). A third randomized controlled trial (Dendrinos, 2009) randomly allocated 85 women to receive low molecular weight heparin plus low-dose aspirin or IVIG. Low molecular weight heparin plus low-dose aspirin (72.5%) resulted in a significantly higher live birth rate than IVIG (39.5%) in treatment of antiphospholipid antibody syndrome in women with recurrent abortion. The American Academy of Allergy, Asthma, and Immunology recommends against use of IVIG to prevent pregnancy loss in women with antiphospholipid syndrome (Orange, 2006).
PURE RED CELL APLASIA (PRCA)
Pure red-cell aplasia is defined as the absence of mature erythroid precursors in a bone marrow that otherwise exhibits normal cellularity. Acquired pure red-cell aplasia may occur in association with neoplasms (such as lymphoproliferative disorders), thymoma, autoimmune disorders, pregnancy, or as a consequence of chronic human parvovirus B19 infection in an immunologically incompetent host. PRCA may also develop after exposure to drugs (erythropoietin or tacrolimus).
There are case reports of effectiveness of IVIG in these conditions, and also in patients with HIV. The Canadian Hematological Expert Panel recommends IVIG for pure red blood cell aplasia if the PRCA is refractory to standard therapy.
RHEUMATIC FEVER, ACUTE
A randomized placebo-controlled trial in 59 patients with rheumatic fever who were treated with either IVIG or placebo revealed that IVIG treatment did not reduce the valvulitis or altered the natural history of the disease (Voss, 2001). A Cochrane Review concludes that IVIG is not indicated in treatment of acute rheumatic fever (Cillers, 2003).
STAPHYLOCOCCAL TOXIC SHOCK SYNDROME
According to the Drug Compendia, the American College of Pediatrics suggests that IGIV may be considered in the management of severe staphylococcal toxic shock syndrome when the infection is refractory to several hours of aggressive therapy, an undrainable focus is present, or the patient has persistent oliguria with pulmonary edema. The American Academy of Allergy, Asthma, and Immunology lists IVIG as “probably beneficial” in staphylococcal toxic shock (Orange, 2006) although they provide no references. A review of therapeutic uses of immunoglobulins in pediatrics (Stiehm, 2010) lists IVIG as probably beneficial, and references from two textbooks (Pickering, 2009; Feigen, 2009), support this use.
STEVENS-JOHNSON SYNDROME
Stevens-Johnson syndrome is a potentially fatal disorder. A prospective non-comparative study of IVIG showed no benefit on mortality or progression (Bachot, 2003). The American Academy of Allergy, Asthma, and Immunology recommends IVIG as “probably beneficial” for treatment of Stevens-Johnson syndrome (Orange, 2006), although the reference given in support of that decision (Trent, 2003) addresses toxic epidermal necrolysis only. The Medical Letter (2006b) states that there is no clear evidence of benefit for Stevens Johnson syndrome, “but [it is]thought to be potentially life-saving. Gurcan and Ahmed in their review of IVIG state, “The current viewpoint is that IVIG may be effective in Stevens-Johnson syndrome and toxic epidermal necrolysis if used very early (within 48 h of onset of clinical features) and at high doses for 3-5 days consecutively (Gurcan, 2007).
THROMBOCYTOPENIA, NEONATAL ALLOIMMUNE
IVIG, to prevent severe intra-uterine thrombocytopenia, given to an expectant mother who had previously delivered an infant with neonatal alloimmune thrombocytopenia, was initially described in a prospective case series of 7 women (Bussel, 1988). Since that time there have been a number of case series and prospective single arm or comparative drug trials of IVIG (Bussel, 1996; Berkowitz, 2006; Berkowitz, 2007), but there have been no randomized controlled trials (RCTs) comparing IVIG to no therapy (Rayment, 2005; Bassler, 2008).
The American Academy of Allergy and Immunology states, “there are anecdotal data supporting the use of IVIG for antenatal therapy of fetomaternal alloimmune thrombocytopenia. Although there are no randomized trials to support this practice, use of IVIG has become routine first-line therapy in this setting.” (Orange, 2006). A Cochrane review of IVIG for antenatal interventions for fetomaternal alloimmune thrombocytopenia concluded, “There are insufficient data from randomized controlled trials to determine the optimal antenatal management of fetomaternal alloimmune thrombocytopenia” (Rayment, 2005). The American College of Obstetrics and Gynecology published a state of the art paper in 2006 stating this therapy is the treatment of choice (Berkowitz, 2006). In a review of neonatal alloimmune thrombocytopenia, (Vinograd, 2010), the authors concluded, “[N]oninvasive approaches and the implementation of risk stratification (including combination therapy of IVIG with steroids and/or the use of more than 1gm/kg/week of IVIG) are appropriate in the management of fetal alloimmune thrombocytopenia. Neither the AHFS nor the Clinical Pharmacology Online compendia have position statements on this therapy. A RCT of antenatal IVIG given in either 2gm/kg/wk or 1gm/kg/wk plus prednisone starting at approximately 20 weeks of gestation, in women with very high risk, high risk and standard risk for neonatal alloimmune thrombocytopenia was initiated in 2001 (expected completion date Feb 2012) at Weill Medical College of Cornell University (NCT00194987), but results of the full study are not yet available. The subset of 73 women in the standard risk group (defined as women with documented alloimmune thrombocytopenia who had not delivered an infant with an intracranial hemorrhage in a prior pregnancy) showed “excellent” outcomes in both groups (Berkowitz, 2007).
TRANSPLANTATION, ANTIBODY MEDIATED REJECTION
One RCT of 30 patients published in 2001 suggested that IVIg is at least as good as anti-CD3 in combating corticosteroid-resistant rejection of kidney transplants (Casadei, 2001). Later, in 2003-4, findings from the NIH IG02, a double-blind placebo-controlled trial, were published (Jordan, 2003). The trial randomized 101 highly sensitized renal transplant candidates to receive either 4 monthly infusions of IVIg or placebo prior to transplant. If transplanted, additional infusions were given monthly for 4 months. IVIg significantly reduced PRA levels in study subjects compared to placebo, resulting in a higher transplant rate. For example, a total of 24 patients subsequently underwent transplant, 16 in the IVIg group and 8 in the placebo group. There was acceptable graft survival in both groups. Desensitization protocols varied among transplant centers; certain protocols commonly used are referred to as the Cedars-Sinai protocol and the Johns Hopkins protocol. The Cedars-Sinai protocol consisted of high-dose IVIg (2 g/kg) and was offered to patients awaiting either a deceased or live donor (Jordan, 2003). The Johns Hopkins protocol consisted of low-dose IVIg (100 mg/kg) in combination with plasmapheresis with or without treatment with anti-CD-20 (i.e., Rituxan) (Montgomery, 2004).
A retrospective cohort study published in 2009 compared outcomes in pediatric liver transplant patients entered into a multicenter Registry who did (n=336) and did not (n=1,612) receive IVIg within 7 days of transplantation (Bucuvalas, 2009). The investigators assumed that IVIg given within this timeframe was used for prophylaxis of antibody mediated rejection (AMR), rather than for treatment. The Kaplan-Meier probability of patient survival was not significantly different between groups (hazard ratio [HR]: 0.97, 95% CI: 0.71-1.39). However, the risk of graft rejection was significantly lower in patients treated with immunoglobulin. In the first 3 months after transplant, 31% of patients who received immunoglobulin and 40% of those not treated had an episode of graft rejection (p=0.02). Similarly, the proportion of patients with 2 or more episodes of graft rejection was significantly lower among those who received immunoglobulin (13.1%) than those who did not (19.2%), p=0.009. Patients were not randomized to treatment group, and there may have been differences in those treated or not treated with immunoglobulin that affected outcomes.
A variety of protocols also have been developed for the treatment of AMR, often in combination with other therapies, such as plasmapheresis or anti-CD-20 (Casadei, 2001; Ibernon, 2005; Jordan, 2005; Lehrich, 2005). The majority of studies of IVIg in the transplant setting are retrospective case series from single institutions. Therefore, it is not possible to compare immunomodulatory regimens to determine their relative efficacy. Nevertheless, in part based on the large volume of literature published on this subject, it appears that IVIg is a component of the standard of care for the management of AMR.
VON WILLEBRAND’S DISEASE, ACQUIRED
The Canadian IVIG Hematology Expert Panel does not recommend IVIG for routine use in the treatment of acquired Von Willebrand’s disease, but states “IVIG may be considered one option among adjunctive therapies in the treatment of acquired von Willebrand’s disease in urgent situations (e.g., active bleeding or preoperatively) (Robinson, 2007). No other major medical society has published recommendations on the use of IVIG in von Willebrand’s disease. Neither the AHFS nor Clinical Pharmacology Online recommend coverage of IVIG for von Willebrand’s disease.
WEST NILE VIRUS FEVER
The West Nile virus has become endemic in the U.S. since 1999 (Lanciotti, 1999), has been found in mosquitoes, birds, horses, and other animals (Rappole, 2000; Campbell, 2002), and antibodies against West Nile virus have become much more common in the plasma of blood donors. Reports have been published of transmission of the disease following solid organ transplantation (Iwamoto, 2003; Rhee 2011). There is no specific treatment for West Nile virus infection, and in most cases the disease is self-limited and treated with supportive care (although some have predicted long-term neurological deficit (Sejvar, 2007). But in persons who are immunosuppressed, or who are elderly, are at risk of fatal meningoencephalitis. There are single and multi-case reports of use of IVIG with high specific antibody titers against West Nile virus with apparent clinical improvement (Shimoni, 2001; Hamdan, 2002; Haley, 2003; Makhoul, 2009; Saqueib, 2008; Rhee, 2011).
Off-label indications covered in the policy are considered eligible for coverage based on one or more of the following:
2019 Update
A literature search conducted through October 2019 did not reveal any new information that would prompt a change in the coverage statement.
2020 Update
A literature search conducted through October 2020 did not reveal any new information that would prompt a change in the coverage statement.
2021 Update
A literature search conducted through October 2021 did not reveal any new information that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2024. Additional citations added. Criteria updated and policy reformatted.
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2025. Criteria updated (removed duration of authorization) and policy reformatted.
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Voss LM, Wilson NJ, Neutze JM, et al.(2001) Intravenous immunoglobulin in acute rheumatic fever: a randomized controlled trial. Circ 2001; 103(3):401-6. Abdou NI, Greenwell CA, Mehta R, Narra M, Hester JD, Halsey JF(2009) Efficacy of intravenous gammaglobulin for immunoglobulin G subclass and/or antibody deficiency in adults. Int Arch Allergy Immunol. 2009; 149(3): 267. Epub 2009 Feb 12. Achilli C, Duran-Retamal M, Saab W, et al.(2018) The role of immunotherapy inin vitro fertilization and recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2018 Nov;110(6):1089-1100. doi: 10.1016/j.fertnstert.2018.07.004. PMID: 30396553 ACOG Practice Bulletin(2016) Thrombocytopenia in pregnancy. Number 166, September 2016. Clinical management guidelines for obstetrician-gynecologists. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2016 Sep;128(3):e43-53. Agrawal AG, Petersen LR.(2003) Human immunoglobulin as a treatment for West Nile virus infection. J Infect Dis 2003; 188:1. Al-Mayouf SM, Laxer RM, Schneider R, et al.(2000) Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety. J Rheumatol 2000; 27(10):2498-503. Alabdali M, Barnett C, Katzberg H, et al.(2014) Intravenous immunoglobulin as treatment for myasthenia gravis: current evidence and outcomes. Expert Rev Intravenous immunoglobulin as treatment for myasthenia gravis: current evidence and outcomes. Expert Rev. Alarcon PA, Matthay KK, London WB, Naranjo A, Tenney SC, Panzer JA, Hogarty MD, Park JR, Maris JM, Cohn SL.(2018) Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial. Lancet Child Adolesc Health. 2018;2(1):25. Epub 2017 Nov 3 Alcock GS, Liley H.(2002) Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev. 2002(3):CD003313. PMID 12137687 Am Society of Reproductive Medicine.(1998) Intravenous Immunoglobulin (IVIG) and Recurrent Spontaneous Pregnancy Loss: A Practice Committee Report; A Committee Opinion. http://www.asrm.org/Media/Practice/ivig.html. 1998; Accessed October 2002. Ameratunga R, Ahn Y, Steele R, Woon ST.(2019) Transient hypogammaglobulinaemia of infancy: many patients recover in adolescence and adulthood. Clin Exp Immunol 2019; 198:224. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia.(2004) Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114:297. American Society for Reproductive Medicine, Birmingham, Alabama, USA.(2012) Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012 Nov;98(5):1103-11. doi: 10.1016/j.fertnstert.2012.06.048. Epub 2012 Jul 24. American Society of Hematology(2020) Guidelines for Sickle Cell Disease: Transfusion support. Blood Adv 2020 Jan 28 (4) 327-55. Ammann EM, Haskins CB, Fillman KM, et al.(2016) Intravenous immune globulin and thromboembolic adverse events: A systematic review and meta-analysis of RCTs. Intravenous immune globulin and thromboembolic adverse events: A systematic review and meta-analysis of RCTs. Ann Neurol 1994; 36(6):838-45.(2008) EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases. European J Neurology, 2008; 15:893-908. Antonelli A, Saracine A, et al.(1992) High-dose intravenous immunoglobulin treatment in Graves’ ophthalmopathy. Acta Endocrinol 1992 (126): 13-23. Ariizumi M, Baba K et al.(1987) Immunoglobulin therapy in the West syndrome. Brain Dev 1987 (9): 422-5. Azulay JP, Blin O, Pouget J, et al.(1994) Intravenous immunoglobulin treatment in patients with motor neuron syndromes associated with anti-GM1 antibodies: a double-blind, placebo-controlled study. Neurology 44:429–432. Bain PG, Motomura M, Newsom-Davis J, Misbah SA, Chapel HM, Lee ML, Vincent A, Lang B.(1996) Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton Myasthenic syndrome. Neurology. 1996;47(3):678. Ballow M, Paris K, de la Morena M.(2018) Should Antibiotic Prophylaxis Be Routinely Used in Patients with Antibody-Mediated Primary Immunodeficiency. J Allergy Clin Immunol Pract 2018; 6:421 Barker RA, Marsden CD.(1997) Successful treatment of stiff man syndrome with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 1997; 62:426. Barron SJ, Del Vecchio MT, Aronoff SC.(2015) Intravenous immunoglobulin in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: a meta-analysis with meta-regression of observational studies Int J Dermatol. Jan 2015;54(1):108-115. PMID 24697283 Branch DW, Peaceman AM, Druzin M, et al.(2000) A multicenter, placebo controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group Am J Ob Gyn 2000; 182(1 Pt 1):122-7. Bruno C, Sotgia F, et al.(2012) Caveolinopathies. http://www.ncbi.nlm.nih.gov/books?term=Caveolinopathies+AND+gene%5Bbook%5D. Bucciarelli S, Espinosa G, Cervera R, et al.(2006) Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum. Aug 2006;54(8):2568-2576. PMID 16868979 Bucuvalas JC, Anand R.(2009) Treatment with immunoglobulin improves outcome for pediatric liver transplant recipients. Liver Transpl 2009; 15(11):1564-9. Bussel JB, Berkowitz RL, Hung C, et al.(2010) Intracranial hemorrhage in alloimmune thrombocytopenia: stratified management to prevent recurrence in the subsequent affected fetus. Am J Obstet Gynecol. 2010 Aug;203(2):135.e1-14. Bussel JB, Berkowitz RL, Lynch L, et al.(1996) Antenatal management of alloimmune thrombocytopenia with intravenous immunoglobulin: a randomized trial of the addition of low dose steroid to intravenous gammaglobulin. Am J Ob Gyn 1996; 174(5):1414-23. Bussel JB, Cunningham-Rundles C, Abraham C.(1986) Intravenous treatment of autoimmune hemolytic anemia with very high dose gammaglobulin. Vox Sang 1986; 51:264. Cantoni N, Weisser M, et al.(2009) Infection prev strategies in a stem cell transplant unit: impacto of change of care in isolation practice and routine use of high dose intraven immunoglobulins on infectious complications and transplant related mortality. Eur J Haematol, 2009:83:130-8. Casadei DH, del C Rial M, Opelz G, et al.(2001) A randomized and prospective study comparing treatment with high dose intravenous immunoglobulin with monoclonal antibodies for rescue of kidney grafts with steroid resistant rejection. Transplantation 2001; 71(1):53-8. Cats EA, van der Pol WL, Piepers S, et al.(2010) Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy. Neurology 2010; 75:818. Centers for Disease Control and Prevention.(2009) Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children. MMWR 2009;58(No. RR-11):11-12. Cervera R, Rodriguez-Pinto I, G Espinosa on behalf of the Task Force on Catastrophic Antiphospholipid Syndrome.(2014) Catastrophic antiphospholipid syndrome: task force report summary. Lupus 2014; 23:1283. Chandesris MO, Melki I, Natividad A, et al.(2012) Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore) 2012; 91:e1. Chapel HM, Lee M, Hargreaves R, Pamphilon DH, Prentice AG.(1994) Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma. Lancet. 1994;343(8905):1059. Christiansen OB, Kolte AM, Krog MC, et al.(2019) Treatment with intravenous immunoglobulin in patients with recurrent pregnancy loss: An update. J Reprod Immunol. 2019 Jun;133:37-42. doi: 10.1016/j.jri.2019.06.001. Epub 2019 Jun 18. PMID: 31238263 Clin Microbial Infect, 2003; 9:333-8. (1999) Immunosuppressive treatment of rippling muscles in patients with myasthenia gravis. Neuromuscul Disord, 1999; 9:604-7. CMS(2002) Medicare coverage policy #CAG-00109N. http://cms.hhs.gov/ coverage/8b3-kkk.asp; 2002. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia, Gale RP, Chapel HM, et al.(1988) Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. N Engl J Med 1988; 319:902. Cordonnier C, Chevret S, et al.(2003) Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled, multicenter trial. Ann Int Med, 2003; 139:8-18. Cosi V, Lombardi M, Piccolo G, Erbetta A.(1991) Treatment of myasthenia gravis with high-dose intravenous immunoglobulin. Acta Neurol Scand. 1991;84(2):81. Crabol Y, Terrier B, Rozenberg F, Pestre V, Legendre C, Hermine O, Montagnier-Petrissans C, Guillevin L, Mouthon L, Groupe d'experts de l'Assistance Publique-Hopitaux de Paris.(2013) Intravenous immunoglobulin therapy for pure red cell aplasia related to human parvovirus b19 infection: a retrospective study of 10 patients and review of the literature. Clin Infect Dis. 2013;56(7):968. Epub 2012 Dec 12. Cunningham-Rundles, C.(2023) Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults. UpToDate, Notarangelo, L. (Ed), Waltham, MA. Accessed on January 18, 2023. Dalakas MC, Fujii M, Li M, et al.(2001) High dose intravenous immune globulin for stiff-person syndrome. NEJM 2001; 345:1870-6. Dalakas MC, Illa I, Dambrosia JM, et al.(1993) A controlled trial of high dose intravenous immune globulin infusions as treatment for dermatomyositis. NEJM 1993; 329(27):1993-2000. Dalakas MC, Koffman B, Fujii M, et al.(2001) A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 2001; 56(3):323-7. Dalakas MC, Quarles RH, Farrer RX, et al.(1996) A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol 1996; 40(5):792-5. Dalakas MC, Sonies B, Dambrosia J, et al.(1997) Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study. Neurology 1997; 48(3):712-6. Dalakas MC.(2024) Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA, 2004; 291:2367-75. Dalal, I. and Roifman, C.M.(2023) Transient hypogammaglobulinemia of infancy.Orange, J.S. (Ed). Transient hypogammaglobulinemia of infancy.Orange, J.S. (Ed). Danieli MG, Malcangi G, Palmieri C, et al.(2002) Cyclosporin A and intravenous immunoglobulin treatment in polymyositis/dermatomyositis. Ann Rheum Dis 2002; 61:37-41. Darabi K, Abdel-Wahab O, Dzik WH.(2006) Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion, 2006; 46:741-53. Darenberg J, Ihendyane N, Sjolin J, et al.(2003) Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis. Aug 01 2003;37(3):333-340. PMID 12884156 Dello Strologo L, Murer L, Guzzo I, et al.(2017) Renal transplantation in sensitized children and young adults: a nationwide approach. Nephrol Dial Transplant 2017; 32:191. Derman BA, Schlei Z. et al .(2021) Changes in Intravenous immunoglobulin Usage for hypogammaglobulinemia After Implementation of a Stewardship Program. JCO Oncol. Pract 2021 (17): e445-53. Dogu F, Ikinciogullari A, Babacan E.(2004) Transient hypogammaglobulinemia of infancy and early childhood: outcome of 30 cases. Turk J Pediatr 2004; 46:120. Donofrio PD, Berger A, et al.(2009) Consenus Statement: the use of intravenousl immunoglobulin in the treatment of neuromuscular conditions report of the AANEM ad hoc committee. Muscle Nerve, 2009; 40:890-900. Douzinas EE, Pitaridis MT, Louris G, et al.(2000) Prevention of infection in multiple trauma patients by high-dose intravenous immunoglobulins. Crit Care Med 2000; 28(1):8-15. Drulovic J, Andrejevic S, Bonaci-Nikolic B, Mijailovic V.(2011) Hashimoto's encephalopathy: a long-lasting remission induced by intravenous immunoglobulins. Vojnosanit Pregl 2011; 68:452. Dyck PJ, Litchy WJ, Kratz KM, et al.(1994) A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 1994; 36(6):838-45. Eftimov F, Winer JB, Vermeulen M, et al.(2013) Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2013; :CD001797. Eid AJ, Ardura MI.(2019) Human parvovirus B19 in solid organ transplantation: Guidelines from the American society of transplantation infectious diseases community of practice. AST Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13535. Epub 2019 Apr 11. Erlewyn-Lajeunesse MD.(2000) Hyperimmunoglobulin-E syndrome with recurrent infection: a review of current opinion and treatment. Pediatr Allergy Immunol 2000; 11:133. Farm AG.(2001) Recent advances in the management of adult myositis. Expert Opin Investig Drugs 2001; 10:1265-77. Fazekas F, Lublin FD, Li D, Freedman MS, PRIVIG Study Group, UBC MS/MRI Research Group, et. al.(2008) Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology. 2008; 71(4):265 Feasby T, Banwell B, et al.(2007) Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Pract, 2007; 21 Suppl 1:S57-S107. Federici AB.(2005) Use of intravenous immunoglobulin in patients with acquired vonWilliebrand Syndrome. Hum Immunol. 2005 Apr;66(4):422-30. doi: 10.1016/j.humimm.2005.01.031. Federico P, Imbimbo M, Buonerba C, Damiano V, Marciano R, Serpico D, Di Lorenzo G, Palmieri G.(2010) Is hypogammaglobulinemia a constant feature in Good's syndrome. International Journal of Immunopathology and Pharmacology. 2010 Oct;23(4):1275-9. Federico P, Zochodne DW, Hahn AF, et al.(2000) Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study. Neurology 2000; 55(9):1256-62. Fei Song & Hanny Al-Samkari.(2021) Management of Adult Patients with Immune Thrombocytopenia (ITP): A Review on Current Guidance and Experience from Clinical Practice. Journal of Blood Medicine, 12:, 653-664, DOI: 10.2147/JBM.S259101. Fekri S, Soheilian M, Rahimi-Ardabili B.(2020) J Intravenous Immunoglobulin for Mang of Non paraneoplastic Auto immune Retinopathy. J Ophthalmic Vis Res. 2020 Apr 6;15(2):246-251. doi: 10.18502/jovr.v15i2.6743. eCollection 2020 Apr-Jun. Ferguson D, Hutton B, et al.(2005) Use of intravenous immunoglobulin for treatment of neurologic conditions: a systematic review. Transfusion Pract, 2005; 45:1640-57. Flores G, Cunningham-Rundles C, Newland AC, et al.(1993) Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol. Dec 1993;44(4):237-242. PMID 8237993. Fox C, Martin W, Somerset DA, et al.(2008) Early intraperitoneal transfusion and adjuvant maternal immunoglobulin therapy in the treatment of severe red cell alloimmunization prior to fetal intravascular transfusion. Fetal Diagn Ther 2008; 23:159. Franchini M, Mannucci PM(2020) Acquired von Willebrand syndrome: focused for hematologists. Haematologica 2020 (105): 2023. Gadian J, Kirk E, Holliday K, et al.(2017) Systematic review of immunoglobulin use in paediatric neurological and neurodevelopmental disorders. Dev Med Child Neurol 2017; 59:136. Gajdos J, Chevret S, Toyka KV.(2012) Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2012;12:CD002277. Gajdos P, Chevret S, Clair B, et al.(1997) Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol 1997; 41(6):789-96. Gajdos P, Tranchant C, et al.(2005) Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-bline clinical trial. Arch Neurol, 2005; 62:1689-93. Gamm H, Huber C et al.(1994) Intravenous immune globulin in chronic lymphocytic leukaemia. Clin Exp Immunol 1994 (97): 17-20. Genevay S, Saudan-Kister A, Guerne PA.(2001) Intravenous gammaglobulins in refractory polymyositis: lower dose for maintenance treatment is effective. Ann Rheum Dis 2001; 60:635-6. Gnann JW Jr, Agrawal A, Hart J, et al.(2019) Lack of Efficacy of High-Titered Immunoglobulin in Patients with West Nile Virus Central Nervous System Disease. Emerg Infect Dis 2019; 25:2064. Godeau B, Caulier MT, Decuypere L, et al.(1999) Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w. Br J Haematol 1999; 107:716. Gold R, Stangel M, Dalakas MC.(2007) Drug Insight: the use of intravenous immunoglobulin in neurology-therapeutic considerations and practical issues. Nat Clin Prac Neurol, 2007; 3:36-44. Gomard-Mennesson E, Ruivard M, Koenig M, Woods A, Magy N, Ninet J, Rousset H, Salles G, Broussolle C, Seve P.(2006) Treatment of isolated severe immune hemolytic anaemia associated with systemic lupus erythematosus: 26 cases. Lupus. 2006;15(4):223 Goodin DS, Frohman EM, Garmany GP Jr, Halper J, Likosky WH, Lublin FD, Silberberg DH, Stuart WH, van den Noort(2002) Disease modifying therap in MS: report of the Therap and Tech Assess Subcom of the AA of Neuro and the MS Council for Clin Prac Guidelines, Therp and Tech AssessSubcom of the AA of Neuro and the MS Council for Clin Prac Guidelines. Neurology. 2002; 58(2):169 Gorson, KC et al.(2002) Efficacy of intravenous immunoglobulin in patients with IgG monoclonal gammopathy and polyneuropathy. Archives of Neurology 2002; 59(5): 766-72. Gottfried I, Seeber A, Anegg B, et al.(2000) High dose intravenous immunoglobulin (IVIG) in dermatomyositis: clinical responses and effect on sIL-2R levels. Eur J Derm 2000; 10(1):29-35. Guy J, Aptsiauri N.(1999) Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol. 1999;117(4):471. Hahn AF, Bolton CF, Zochodne D, et al.(1996) Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study. Brain 1996; 119(Pt 4):1067-77. Hanitsch L, Baumann U, Boztug K, Burkhard-Meier U, Fasshauer M, Habermehl P, Hauck F, Klock G, Liese J, Meyer O, Muller R.(2020) Treatment and management of primary antibody deficiency: German interdisciplinary evidence-based consensus guideline. European journal of immunology. 2020 Oct;50(10):1432-46. Hargreaves RM, Lea JR, et al.(1995) Immunological factors and risk of infection in plateau phase myeloma. J Clin Pathol, 1995; 48(3):260-6. Heimall, J.(2023) Severe combined immunodeficiency (SCID): An overview. Puck, J.M. (Ed). UpToDate, Waltham, MA. Accessed on January 27, 2023. Hernandez-Trujillo, V.(2023) Agammaglobulinemia.Puck. J.M. (Ed). UpToDate, Waltham, MA. Accessed on January 27, 2023. Hoang J, Krisl J, Moaddab M, Nguyen DT, Graviss EA, Hussain I, Kassi M, Yousefzai R, Kim J, Trachtenberg B, Bhimaraj A, Guha A.(2022) Intravenous immunoglobulin in heart transplant recipients with mild to moderate hypogammaglobulinemia and infection. Clin Transplant. 2022 Apr;36(4):e14571. doi: 10.1111/ctr.14571. Epub 2022 Jan 6. PMID: 34964505. Huang YC, Li YC, Chen TJ.(2012) The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol 2012; 167:424. Huang YH, Chen HC, Huang KW, et al.(2015) Intravenous immunoglobulin for postpolio syndrome: a systematic review and meta-analysis. BMC Neurol. 2015;15:39. PMID 25886512 Hughes RA, Donofrio P, Bril V, et al.(2008) Intravenous immune globulin (10% caprylate-chromatography purified) for treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized placebo-controlled trial. Lancet Neurol, 2008; 7:136-144. Lancet Neurol, 2008; 7:136-144. Hundt M, Manger K, Dorner T, et al.(2000) Treatment of acute exacerbation of systemic lupus erythematosus with high-dose intravenous immunoglobulin. Rheumatology (Oxford) 2000; 39(11):1301-2. Ibernon M, Gil-Vernet S, Carrera M et al.(2005) Therapy with plasmapheresis and intravenous immunoglobulin for acute humoral rejection in kidney transplantation. Transplant Proc 2005; 37(9):3743-5. Illa I.(2005) IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status. J Neurol. 2005; 252 Suppl 1:I14 Jablonowska B, Selbing A, Palfi M et al.(1999) Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Hum Reprod 1999; 14(3):838-41. Jacob S, Rajabally YA.(2005) Hashimoto's encephalopathy: steroid resistance and response to intravenous immunoglobulins. J Neurol Neurosurg Psychiatry 2005; 76:455. Jayne DR, Chapel H, Adu D, et al.(2000) Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000; 93(7):433-9. Joint Task Force of the EFNS and the PNS.(2010) EFNS/PNS Guideline on management of multifocal motor neuropathy. Report of a Joint Task Force of the EFNS and the PNS - first revision. EFNS/PNS Guideline on management of multifocal motor neuropathy. Report of a Joint Task Force of the EFNS and the PNS - first revision. Jordan S, Tyan D, Stablein D et al.(2004) Eval of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult pat with end-stage renal disease: report of the NIH IG02 trial.J Am Soc Nephrol 2004; 15(12):3256-62. J Am Soc Nephrol 2004; 15(12):3256-62. Jordan S, Vo A, Tyan D et al.(2005) Current approaches to treatment of antibody-mediated rejection. Pediatr Transplant 2005; 9(3):408-15. Jordan SC, Quartel AW, Czer LS, et al.(1998) Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation 1998; 66(6):8005. Jordan SC, Vo AA, Nast CC et al.(2003) Use of high-dose human intravenous immunoglobulin therapy in sensitized patients awaiting transplantation: the Cedars-Sinai experience. Clin Transpl 2003:193-8. Joshi AY, Iyer VN, Boyce TG, Hagan JB, Park MA, Abraham RS.(2009) Elevated serum immunoglobulin E (IgE): when to suspect hyper-IgE syndrome-A 10-year pediatric tertiary care center experience. Allergy Asthma Proc. 2009 Jan-Feb;30(1):23-7. doi: 10.2500/aap.2009.30.3193. PMID: 19331717. Joud Hajjar, Nguyen AL, Constantine G, et al.(2020) Prophylactic Antibiotics Versus Immunoglobulin Replacement in Specific Antibody Deficiency. J Clin Immunol 2020; 40:158. Kahaly G, Pitz S, Muller-Forell W, Hommel G.(1996) Randomized trial of intravenous immunoglobulins versus prednisolone in Graves' ophthalmopathy. Clinical & Experimental Immunology. 1996 Nov;106(2):197-202. Karlson EW, Sudarsky L, Ruderman E, et al.(1994) Treatment of stiff-man syndrome with intravenous immune globulin. Arthritis Rheum 1994; 37:915. Kaul R, McGeer A, Norrby-Teglund A, et al.(1999) Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome--a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis. Apr 1999;28(4):800-807. PMID 10825042 Kazatchkine MD, Kaveri SV.(2001) Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. NEJM 2001; 345:747-755. Kiehl MG, Stoll R, Broder M, et al.(1996) A controlled trial of intravenous immune globulin for the prevention of serious infections in adults with advanced human immunodeficiency virus infection. Arch Intern Med 1996; 156(22):2545-50. Kishiyama JL, Valacer D, Cunningham-Rundles C, et al.(1999) A multicenter, randomized, double blind, placebo controlled trial of high dose intravenous immunoglobulin for oral corticosteroid dependent asthma. Clin Immunol 1999; 91(2):126-33. Knutsen, A.P.(2023) Knutsen, A.P. UpToDate, Waltham, MA. Accessed on January 11, 2023. Koumoutsea EV et al.(2021) Intravenous immunoglobulin in the management of Severe Early Onset Red Blood Cell Alloimmunization. Blood 2021 (138): 2140. Kress HG, Scheidewig C, Schmidt H, et al.(1999) Reduced incidence of postoperative infection after intravenous administration of an immunoglobulin A- and immunoglobulin M-enriched preparation in anergic patients undergoing cardiac surgery. Crit Care Med 1999; 27(7):1281-7. Kurtzman G, Frickhofen N, Kimball J, Jenkins DW, Nienhuis AW, Young NS.(1989) Pure red-cell aplasia of 10 years' duration due to persistent parvovirus B19 infection and its cure with immunoglobulin therapy. N Engl J Med. 1989;321(8):519. Lafferty TE, Smith JB, Schuster SJ, DeHoratius RJ.(1997) Treatment of acquired factor VIII inhibitor using intravenous immunoglobulin in two patients with systemic lupus erythematosus. Arthritis Rheum 1997; 40:775. Lancaster, E.(2016) The Diagnosis and Treatment of Autoimmune Encephalitis. J Clin Neurol. 2016 Jan;12(1):1-13. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712273/pdf/jcn-12-1.pdf. Lange, DJ, et al.(2023) Multifocal motor neuropathy. Shefner, J.M. (Ed), UpToDate, Waltham, MA. Accessed on January 27, 2023. Lee CY, Lin WC et al(2016) Repeated cycles of high-dose intravenous immunoglobulin and plasmapheresis for treatment of late antibody-mediated rejection of renal transplants. J Formosan Med Assn 2016 (115): 845-52. Lee HY, Lim YL, Thirumoorthy T, Pang SM.(2013) Lee HY, Lim YL, Thirumoorthy T, Pang SM. Br J Dermatol 2013; 169:1304. Leger JM, Chassande B, Musset L, et al.(2001) Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebo-controlled study. Brain 124:145–153. LeHoang P, Cassoux N, George F, et al.(2000) Intravenous immunoglobulin (IVIg) for the treatment of bird shot retinochoroidopathy. Ocul Immunol Inflamm 2000; 8(1):49-57. Lehrich R, Rocha P, Reinsmoen N et al.(2005) Intravenous immunoglobulin and plasmapheresis in acute humoral rejection: Experience in renal allograft transplantation. Hum Immunol 2005; 66(4):350-8. Levy Y, Sherer Y, Ahmed A, et al.(1999) A study of 20 SLE patients with intravenous immunoglobulin clinical and serologic response. Lupus 1999; 8(9):705-12. Liew W, Powell C, Sloan S, et al.(2014) Comparison of plasmapheresis and intravenous immunoglobulin as maintenance therapies for juvenile myasthenia gravis. JAMA Neurol. 2014 May;71(5):575-80. Limaye, A.P., Brennan, D.C.(2024) Specific antibody deficiency.Vella, J., Blumberg, E.A. (Ed), UpToDate, Waltham, MA. Accessed on May 5th, 2024. Linner A, Darenberg J, Sjolin J, et al.(2014) Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study. Clin Infect Dis. Sep 15 2014;59(6):851-857. PMID 24928291 Lockwood CM(1996) New treatment strategies for systemic vasculitis: the role of intravenous immune globulin therapy. Clin Exp Immunol 1996; 104(sup 1):77-82. Lok KZ, Basta M, Manzanero S, Arumugam TV.(2015) Intravenous immunoglobulin (IVIg) dampens neuronal toll-like receptor-mediated responses in ischemia. Journal of neuroinflammation. 2015 Dec;12(1):1-6. Louis D, More K, Oberoi S, et al.(2014) Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. Jul 2014;99(4):F325-331. PMID 24514437 Ludwig H, Zojer N.(2007) Supportive care in multiple myeloma. Best Pract Res Clin Haematol, 2007; 20(4):817-35. Luke PP, Scantlebury VP, Jordan ML, et al.(2001) Reversal of steroid- and anti-lymphocyte antibody resistant rejection using intravenous immunoglobulin (IVIG) in renal transplant recipients. Transplantation 2001; 72(3):419-22. Macintyre EA, Linch DC, Macey MG, et al.(1985) Successful response to intravenous immunoglobulin in autoimmune haemolytic anaemia. Br J Haematol. Jun 1985;60(2):387-388. PMID 4005186. Majer RV, Hyde RD.(1988) High-dose intravenous immunoglobulin in the treatment of autoimmune haemolytic anaemia. Clin Lab Haematol 1988; 10:391. Manuel A and Vasudevan MC.(2021) A Case of Marburg’s Variant of Multiple Sclerosis Successfully Treated with IVIG and mitoxatrone. Ann Indian Acad Neurol 2021 (24): 92-94. Marchioni E, Marinou-Aktipi K, Uggetti C, et al.(2002) Effectiveness of intravenous immunoglobulin treatment in adult patients with steroid-resistant monophasic or recurrent acute disseminated encephalomyelitis. J Neurol 2002; 249:100. Marie I, Hachulla E, Levesque H, et al.(1999) Intravenous immunoglobulins as treatment of life threatening esophageal involvement in polymyositis and dermatomyositis. J Rheumatol 1999; 26:2706-9. Marie I, Menard JF, Hatron PY, Hachulla E, Mouthon L, Tiev K, Ducrotte P, Cherin P.(2010) Intravenous immunoglobulins for steroid-refractory esophageal involvement related to polymyositis and dermatomyositis: a series of 73 patients. Arthritis Care Res (Hoboken). 2010;62(12):1748. Martinez V, Cohen P, Pagnoux C, et al.(2008) Intravenous Immunoglobulins for Relapses of Systemic Vasculitides Associated with Antineutrophil Cytoplasmic Autoantibodies. 2008;58(1):308-17. Matsuura R, Hamano S, Hirata Y, Oba A, Suzuki K, Kikuchi K.(2016) Intravenous immunoglobulin therapy is rarely effective as the initial treatment in Wes Syndrome: A retrospective study of 70 patients. J Neurol Sci. 2016 Sep 15;36:140-4. McNamara DM, Holubkov R, Starling RC, et al.(2001) Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circ 2001; 103(18):2254-9. Memmedova L, Azarsiz E, Edeer Karaca N, et al.(2013) Does intravenous immunoglobulin therapy prolong immunodeficiency in transient hypogammaglobulinemia of infancy? Pediatr Rep 2013; 5:e14. Meriggioli MN.(2007) IVIG in myasthenia gravis. Getting enough bang for the buck. Neurology, 2007; 68:803-4. Mithoowani S, Cervi A, Shah N, et al.(2020) Management of major bleeds in patients with immune thrombocytopenia. J Thromb Haemost 2020; 18:1783. Mlabs, The University of Michigan Department of Pathology.(2017) Immunoglobulin G Subclass Quantitation. Pathology Handbook. https://www.pathology.med.umich.edu/handbook/#/details/548. Accessed January 11, 2023. Mlabs, The University of Michigan Department of Pathology.(2023) Immunoglobulin Quantitation. https://mlabs.umich.edu/tests/immunoglobulin-quantitation-0. Accessed January 12, 2023. Mlabs, The University of Michigan Department of Pathology.(2023) Tetanus Toxoid IgG Antibody. Pathology Handbook. https://www.pathology.med.umich.edu/handbook/#/details/548. Accessed January 11, 2023. Montgomery R, Zachary A.(2004) Transplanting patients with a positive donor-specific crossmatch: a single center’s perspective. Pediatr Transplant 2004; 8(6):535-42. Moore JC, Arnold DM et al,(2007) Intravenous immunoglobulin as an adjunct to plasma exchange for the treatment of chronic thrombotic thrombocytopenic purpura. Vox Sang 2007 (93): 173-5. Mouthon L, Lortholary O.(2003) Mouthon L, Lortholary O. Clin Microbial Infect, 2003; 9:333-8. Mueller-Eckhardt C, Kiefel V.(1988) High-dose IgG for post-transfusion purpura-revisited. Blut. 1988; 57(4):163 Multiple authors.(2009) A randomized double-blind trial of intravenous immunoglobulin for pemphigus. Pemphigus Study Group. J Am Acad Dermatol. 2009;60(4):595. National Comprehensive Cancer Network (NCCN).(2021) Management of Immunotherapy-Related Toxicities v.3.2021. Accessed at https://www.nccn.org/professionals/drug_compendium/content/. Accessed September 15, 2021. Newburger JW, Takahashi M, Beiser AS, et al.(1991) A single intravenous infusion of gamma globulin compared with four infusions in the treatment of acute Kawasaki syndrome. NEJM 1991; 324(23):1633-9. Newburger JW, Takahashi M, Gerber MA, et al.(2004) Diag, 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, AHA Circulation 2004; 110:2747. Newsom-Davis J, Mills KR.(1993) Immunological associations of acquired neuromyotonia (Isaacs' syndrome) Report of five cases and literature review. Brain. 1993 Apr 1;116(2):453-69. Norrby-Teglund A, Muller MP, McGeer A, et al.(2005) Successful management of severe group A streptococcal soft tissue infections using an aggressive medical regimen including intravenous polyspecific immunoglobulin together with a conservative surgical approach. Scand J Infect Dis. 2005;37(3):166-172. PMID 15849047 Nosadini M, Eyre M, Molteni E, et al.(2021) Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis: A Meta-analysis. JAMA Neurol 2021; 78:1333. Noseworthy JH, O’Brien PC, Petterson TM, et al.(2001) A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology 2001; 56(11):1514-22. Noseworthy JH, O’Brien PC, Weinshenker BG, et al.(2000) IV immunoglobulin does not reverse established weakness in MS. Neurology 2000; 55(8):1135-43. Nucci M, Anaissie E.(2009) Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis, 2009; 40:1211-25. Ohlsson A, Lacy JB.(2015) Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev. 2015;3:CD001239. PMID 25815707 Ohmoto A, Fuji S, Shultes KC, Savani BN, Einsele H.(2022) Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia. Bone Marrow Transplantation. 2022 Jun;57(6):874-80 Okulu E, Erdeve O et al.(2022) Intravenous Immunoglobulin Use in Hemolytic Disease Due to ABO incompatibility to Prevent Exchange Transfusion. Frontiers Pediatr 2022 (28). Olinder-Nielsen AM, Granert C, Forsberg P, Friman V, Vietorisz A, Bjorkander J.(2007) Immunoglobulin prophylaxis in 350 adults with IgG subclass deficiency and recurrent respiratory tract infections: a long-term follow-up. Scand J Infect Dis. 2007;39(1):44 Opal P.(2022) Ataxia-telangiectasia. Patterson, M.C. (Ed), UpToDate, Waltham, MA. Accessed January 27, 2023. Orange JS, et al(2012) Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2012 Sep;130(3 Suppl):S1-24. doi: 10.1016/j.jaci.2012.07.002. PMID: 22935624. Orange JS, et al(2017) Multispecialty rating of evidence-based conditions for intravenous immunoglobulin therapy using a 3-axis prioritization algorithm. Am Health Drug Benefits 2017(10): 134-142 Ortiz JF, Ghani MR, Cox AM, Tambo W, Bashir F, Wirth M, Moya G.(2020) Stiff-person syndrome: a treatment update and new directions. Cureus. 2020 Dec 9;12(12). Otani IM, Lehman HK, Jongco AM, Tsao LR, Azar AE, Tarrant TK, Engel E, Walter JE, Truong TQ, Khan DA, Ballow M.(2022) Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: a work group report of the AAAAI primary immunodeficiency and altered immune response committees. Journal of Allergy and Clinical Immunology. 2022 May 1;149(5):1525-60. Ouwehand WH, Smith G, Ranasinghe E.(2000) Management of severe alloimmune thrombocytopenia in the newborn. Arch Dis Child Fetal Neonatal Ed 2000; 82:F173. Ovali F, Samanci N, Ermis B, et al.(1998) Alternative therapies for neonatal autoimmune thrombocytopenia. Vox Sang 1998; 74:198. Park S, Jung CW, Jang JH, Kim SJ, Kim WS, Kim K.(2015) Incidence of infection according to intravenous immunoglobulin use in autologous hematopoietic stem cell transplant recipients with multiple myeloma. Incidence of infection according to intravenous immunoglobulin use in autologous hematopoietic stem cell transplant recipients with multiple myeloma. Park YH.(2022) Diagnosis and management of thrombocytopenia in pregnancy. Blood Res. 2022 Apr 30;57(S1):79-85. doi: 10.5045/br.2022.2022068. PMID: 35483931; PMCID: PMC9057658. Parks T, Wilson C, Curtis N, et al.(2018) Polyspecific Intravenous Immunoglobulin in Clindamycin-treated Patients With Streptococcal Toxic Shock Syndrome: A Systematic Review and Meta-analysis. Clin Infect Dis 2018; 67:1434. Parks, K.(2022) Specific antibody deficiency. In: UpToDate, Orange. J.S. (Ed), UpToDate, Waltham, MA. Accessed on January 12, 2023. Patwa HS, Chaudhry V, Katzberg H, et al.(2012) Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2012; 78:1009. Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, El-Gamal Y, Harville TO, Hossny E, Mazer B, Nelson R.(2017) Update on the use of immunoglobulin in human disease: a review of evidence. Journal of Allergy and Clinical Immunology. 2017 Mar 1;139(3):S1-46. Plasma Exchange/Sandoglobulin Guillain-Barre Syndrome Trial Group.(1997) Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barre syndrome. Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barre syndrome. Qureshi AI, Choudhry MA, Akbar MS, et al.(1999) Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology 1999; 52(3):629-32. Raanani P, Gafter-Gvili A, et al.(2008) Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol, 2008; 27:770-81. Raanani P, Gafter-Gvili A, Paul M, et al.(2009) Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis. Leuk Lymphoma 2009; 50:764. Rhee C, Eaton EF, Concepcion W, Blackburn BG.(2011) West Nile virus encephalitis acquired via liver transplantation and clinical response to intravenous immunoglobulin: case report and review of the literature. Transpl Infect Dis 2011; 13:312. Robson WL, Fick GH, et al.(1991) The use of immunoglobulin in the treatment of typical hemolytic uremic syndrome. Pediatric Nephrol 1991 (5): 289-92. Roed HG, Langkilde A, Sellebjerg F, Lauritzen M, Bang P, Morup A, Frederiksen JL(2005) A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology. 2005;64(5):804 Ronager J, Ravnborg M, Hermansen I, et al.(2001) Immunoglobulin treatment versus plasma exchange in patients with chronic moderate to severe myasthenia gravis. Artif Organs 2001; 25(12):967-73. Rosenbaum JT, George RK, Gordon C.(1999) The treatment of refractory uveitis with intravenous immunoglobulin. Am J Ophthal 1999; 127(5):545-9. Saha T, Younger ME et al.(2022) Immunoglobulin replacement in Solid Organ transplant patients with hypogammaglobulinemia. J All Clin Immunol. 2022 (145). Sahlas DJ, Miller SP, Guerin M, et al.(2000) Treatment of acute disseminated encephalomyelitis with intravenous immunoglobulin. Neurology 2000; 54:1370. Sakthiswary R, D'Cruz D.(2014) Intravenous immunoglobulin in the therapeutic armamentarium of systemic lupus erythematosus: a systematic review and meta-analysis. Medicine (Baltimore). Oct 2014;93(16):e86. PMID 25310743 Salmun LM, Barlan I, Wolf HM, et al.(1999) Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: a double-blind, placebo-controlled, randomized trial. J Allergy Clin Immunol 1999; 103(5 Pt 1):810-5. Sato K, Hara T, Kondo T, et al.(1991) High-dose intravenous gammaglobulin therapy for neonatal immune haemolytic jaundice due to blood group incompatibility. Acta Paediatr Scand 1991; 80:163. Schoser B, Jacob S, et al.(2009) Immune-mediated rippling muscle disease with myasthenia gravis: a report of seven patients with long-term follow-up in two. Neuromuscul Disord, 2009; 19:223-8. Schwartz RS, Gabriel DA, Aledort LM, et al.(1995) A prospective study of treatment of acquired (autoimmune) factor VIII inhibitors with high-dose intravenous gammaglobulin. Blood 1995; 86:797. Scott JR.(2002) Immunotherapy for recurrent miscarriage. The Cochrane Library; Issue 3; Oxford: Update Software, 2002. Shah SS, Hall M, Srivastava R, et al.(2009) Intravenous immunoglobulin in children with streptococcal toxic shock syndrome. Clin Infect Dis. Nov 01 2009;49(9):1369-1376. PMID 19788359. Shahrizaila N, Lehmann HC, Kuwabara S.(2021) Guillain-Barre syndrome. Lancet 2021; 397:1214. Sharma KR, Cross J, Ayyar DR, et al.(2002) Diabetic demyelinating polyneuropathy responsive to intravenous immunoglobulin therapy. Arch Neurol 2002; 59(5):751-7. Shearer WT, Buckley RH, Engler RJ, et al.(1996) Practice parameters for the diag and management of immunodeficiency. The Clinical and Laboratory Immunology Committee of the AA of Allergy, Asthma, and Immunology (CLIC-AAAAI). Ann Allergy Asthma Immunol 1996; 76:282. Ann Allergy Asthma Immunol 1996; 76:282. Shimoni Z, Bin H, et al.(2012) The clinical response of West Nile virus neuroinvasive disease to intravenous immunoglobulin therapy. Clin Pract 2012 (2): e18. Shrimpton A, Duddridge M, Ziegler-Heitbrock L.(2006) Vaccination with polysaccharide-conjugate-vaccines in adult patients with specific antibody deficiency. Vaccine 2006; 24:3574. Sigra S, Hesselmark E, Bejerot S.(2018) Treatment of PANDAS and PANS: a systematic review. Neurosci Biobehav Rev 2018; 86:51. Skeie GO, Apostolski S, et al.(2006) Guidelines for the treatment of autoimmune neuromuscular transmission disorders. Eur J Neurology, 2006; 13:691-9. Sokos DR, Berger M, Lazarus HM.(2002) Intravenous immunoglobulin: appropriate indications and uses in hematopoietic stem cell transplantation. Biol Blood Bone Marrow Transplant, 2002; 8:117-30. Stratton JD and Warwicker P.(2002) Successful treatment of factor H-related haemolytic uraemic syndrome. Nephrol Dial Transplant 2002 (17): 684-6. The Intravenous Immunoglobulin Collaborative Study Group.(1992) Prophylactic intravenous administration of standard immune globulin as compared with core-lipopolysaccharide immune globulin in patients at high risk of post-surgical infection. NEJM 1992; 327:234-240. Thrombotic Thrombocytopenic Purpura Park SJ, Kim SJ et al.(2008) High-dose Immunoglobulin infusion for Thrombotic Thrombocytopenic Purpura Refractory to Plasma Exchange and Steroid Therapy. Korean J Intern Med 2008 (23): 161-4. Van den Berg LH, Kerkhoff H, Oey PL, et al.(1995) Treatment of multifocal motor neuropathy with high dose intravenous immunoglobulins: a double blind, placebo controlled study. J Neurol Neurosurg Psychiatry 59:248–252. van der Meche FGA, Schmitz PIM, et al.(1992) A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. NEJM 1992; 326:1123-1129. van Schaik IN, Bril V, van Geloven N, Hartung HP, Lewis RA, Sobue G, Lawo JP, Praus M, Mielke O, Durn BL, Cornblath DR, Merkies ISJ; PATH study group.(2018) Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2018 Jan;17(1):35-46. doi: 10.1016/S1474-4422(17)30378-2. Epub 2017 Nov 6. Erratum in: Lancet Neurol. 2018 Jan;17 (1):26. Erratum in: Lancet Neurol. 2018 Aug;17(8):661. Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, et al.(1997) Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med 1997; 103(1):38-43. Wakim M, Alazard M, Yajima A, et al.(1998) High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome. Ann Allergy Asthma Immunol 1998; 81:153. Walgaard C, Jacobs BC, Lingsma HF, et al.(2021) Second intravenous immunoglobulin dose in patients with Guillain-Barre syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol 2021; 20:275. Walter MC, Lochmuller H, Toepfer M, et al.(2000) High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol 2000; 247(1):22-8. Wen YK and Chen ML.(2006) Rescue treatment for cyclosporine-associated hemolytic uremic syndrome with intravenous immunoglobulin. Clin Nephrol 2006 (66): 58-62. Williams KA, Swedo SE, Farmer CA, et al.(2016) Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections. J Am Acad Child Adolesc Psychiatry 2016; 55:860. Win N, Sinha S et al.(2010) Treatment with intravenous immunoglobulin and steroids may correct severe anemia in hyperhemolytic transfusion reactions: case report and literature review. Transfus Med Rev 2010 (24): 64-7. Wolfe GF, Barohn RJ, et al.(2002) Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve, 2002; 26:549-52. Wollenberg A, Thomsen SF, Lacour JP, Jaumont X, Lazarewicz S.(2021) Targeting immunoglobulin E in atopic dermatitis: a review of the existing evidence. World Allergy Organization Journal. 2021 Mar 1;14(3):100519. Zheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, Matsumoto M, Mustafa RA, Pai M, Rock G, Russell L.(2020) ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. Journal of Thrombosis and Haemostasis. 2020 Oct 1;18(10):2486-95. Zinman L, Ng E, Bril V.(2007) IV immunoglobulin in patients with myasthenia gravis. A randomized controlled trial. IV immunoglobulin in patients with myasthenia gravis. A randomized controlled trial. Zuliani L, Nosadini M, Gastaldi M, et. al.(2019) Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations. Neurological Sciences 2019. 40:2017-2030. https://doi.org/10.1007/s10072-019-03930-3. Zwiers C, van der Bom JG, van Kamp IL, et al.(2018) Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment; the PETIT study on severe hemolytic disease of the fetus and newborn. Am J Obstet Gynecol 2018; 219:291.e1. |
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