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Aetna Aetna
Clinical Policy Bulletin:
Parenteral Immunoglobulins
Number: 0206


Policy

  1. Aetna considers the use of intravenous immunoglobulin (IVIG) therapy medically necessary in members with the conditions specified below:

    1. Acquired red cell aplasia

    2. Acute disseminated encephalomyelitis (see Appendix)

    3. Autoimmune mucocutaneous blistering diseases: IVIG is considered medically necessary for members with pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid (a.k.a., cicatrical pemphigoid), and epidermolysis bullosa acquisita if the member has either failed or has contraindications to conventional therapy, or the member has rapidly progressive disease in which a clinical response could not be affected quickly enough using conventional agents.  When indicated for rapidly progressive disease, accepted guidelines indicate that IVIG should be given along with conventional treatment(s) and IVIG should be used only until conventional therapy could take effect.  (See Appendix) Note: IVIG for the treatment of autoimmune mucocutaneous blistering disease is considered medically necessary only for short-term therapy and not as a maintenance therapy

    4. B-cell chronic lymphocytic leukemia (CLL): For persons with hypogammaglobulinemia associated with CLL and recurrent infections or specific antibody deficiency (see Appendix)

    5. Birdshot (vitiligenous) retinochoroidopathy (see Appendix)

    6. Chronic inflammatory demyelinating polyneuropathy (see Appendix)

    7. Churg-Strauss Syndrome (CSS) (allergic granulomatosis): For persons with severe active illness for whom other interventions have been unsuccessful, have become intolerable, or are contraindicated

    8. Dermatomyositis in persons who are resistant to first and second line therapies (see Appendix)

    9. Enteroviral meningoencephalitis (see Appendix)

    10. Guillain-Barré syndrome (GBS) and GBS variants: IVIG is generally accepted as the treatment of choice for persons with Guillain-Barre syndrome, provided that they are so severely affected that they at least require aid to walk, that the disorder is diagnosed during the first 2 weeks of the illness, and that there are no contraindications to IVIG (see Appendix)

    11. Hemolytic disease of newborn, to decrease need for exchange transfusion (see Appendix)

    12. HIV infected children: Bacterial control or prevention (see Appendix)

    13. HIV-associated thrombocytopenia, pediatric or adult: Considered medically necessary when criteria in Appendix are met (see Appendix)

    14. Hyperimmunoglobulinemia E syndrome: For treatment of severe infection (see Appendix)

    15. IgM antimyelin-associated glycoprotein paraprotein-associated peripheral neuropathy

    16. Immune or idiopathic thrombocytopenic purpura (ITP) when a rapid rise in the platelet count is required, such as prior to surgery, to control excessive bleeding, or to defer or avoid splenectomy (see Appendix for criteria for ITP in adults, ITP in children, chronic ITP, and ITP in pregnancy)

    17. Kawasaki disease (see Appendix)

    18. Lambert-Eaton myasthenic syndrome (see Appendix)

    19. Moersch-Woltmann (Stiff-man) syndrome (unresponsive to other therapies) (see Appendix)

    20. Multifocal motor neuropathy: For persons who have progressive, symptomatic multifocal motor neuropathy that has been diagnosed on the basis of electrophysiologic findings that rule out other possible conditions that may not respond to this treatment (see Appendix)

    21. Multiple myeloma (see Appendix)

    22. Myasthenia gravis (see Appendix)

    23. Neonatal alloimmune thrombocytopenia (NAIT) (also known as fetal alloimmune thrombocytopenia or FAIT) (see Appendix)

    24. Neonatal hemochromatosis, prophylaxis (see Appendix)

    25. Opsoclonus-myoclonus (see Appendix)

    26. Paraneoplastic opsoclonus-myoclonus-ataxia associated with neuroblastoma (see Appendix)

    27. Parvovirus B19 infection, chronic, with severe anemia (see Appendix)

    28. Polymyositis in persons who are resistant to first and second line therapies (see Appendix)

    29. Post-transfusion purpura (see Appendix)

    30. Primary humoral immunodeficiency diseases (such as congenital agammaglobulinemia (X-linked agammaglobulinemia), hypogammaglobulinemia, common variable immunodeficiency, X-linked immunodeficiency with hyperimmunoglobulin M, Wiscott-Aldrich syndrome, immunodeficiency with thymoma (Good syndrome), and severe combined immunodeficiency) (see Appendix)

    31. Rasmussen encephalitis (Rasmussen's syndrome) (see Appendix)

    32. Refractory autoimmune hemolytic anemia (see Appendix)

    33. Relapsing-remitting multiple sclerosis (MS) when standard approaches (i.e., interferons) have failed, become intolerable, or are contraindicated (see Appendix) (See also CPB 0264 - Multiple Sclerosis)

    34. Renal transplantation from live donor with ABO incompatibility or positive cross-match, where a suitable non-reactive live or cadaveric donor is unavailable (preparative regimen)

    35. Secondary immunosuppression associated with major surgery (such as cardiac transplants) and certain diseases (extensive burns, or collagen-vascular diseases) (see Appendix)

    36. Selective IgG subclass deficiencies with severe infection for persons meeting selection criteria (see Appendix)

    37. Solid organ transplantation, for suppression of panel reactive anti-HLA antibodies in persons with high panel reactive antibody (PRA) levels to human leukocyte antigens (HLA) prior to transplantation, and for treatment of antibody mediated rejection of solid organ transplants

    38. Staphylococcal toxic shock syndrome (see Appendix)

    39. Stem cell or bone marrow transplantation: IVIG is indicated for prophylaxis in allogeneic or syngeneic transplant recipients within the first 100 days post-transplant; after 100 days post-transplant IVIG is indicated for recipients who are markedly hypogammaglobinemic (IgG level less than 400 mg/dL), or who have CMV, EBV, or RSV infection (see Appendix and CPB 0544 - Immune Globulins for Post-exposure Prophylaxis).  IVIG is also indicated for steroid-resistant graft-versus-host disease in bone marrow transplant recipients 20 years of age or older, in the first 100 days post-transplant, and who are hypogammaglobinemic (IgG level less than 400 mg/dL).

    40. Systemic lupus erythematosus (SLE), for persons with severe active SLE for whom other interventions have been unsuccessful, have become intolerable, or are contraindicated (see Appendix)

    41. Toxic epidermal necrolysis and Steven-Johnson syndrome (see Appendix)

    42. Toxic shock syndrome or toxic necrotizing fasciitis due to group A streptococcus (see Appendix).

  2. Aetna considers subcutaneously administered immunoglobulins as an alternative to intravenous immunoglobulin therapy medically necessary for members who meet the criteria for IVIG set forth above.

  3. Aetna considers intramuscularly administered immunoglobulins (e.g., GamaSTAN S/D) medically necessary as an alternative to intravenous immunoglobulin therapy for conditions associated with hypogammaglobulinemia that meet the criteria for IVIG set forth above.  Intramuscular formulations of immune globulin are also considered medically necessary for the following indications: prophylaxis of hepatitis A; prevention or modification of measles (rubeola) in persons exposed fewer than 6 days previously; passive immunization against varicella in immunosuppressed patients; and prophylaxis of rubella in pregnancy when therapeutic abortion is not an option.  See CPB 0544 - Immune Globulins for Postexposure Prophylaxis.

  4. Aetna considers the use of IVIG experimental and investigational for all other clinical conditions because its effectiveness for indications othe than the ones listed above has not been established.  See Appendix for a current list of such indications (not an all-inclusive list).

  5. Least Cost Medically Necessary Brands of Parenteral Immunoglobulins:

    There are several brands of parenteral immunoglobulins on the market (see appendix).  There is a lack of reliable evidence that any one brand of parenteral immunoglobulin is superior to other brands for medically necessary indications.  Gammaplex brand of parenteral immunoglobulin ("least cost brand of parenteral immunoglobulin") is less costly to Aetna.  Consequently, because other brands (e.g., Bivigam, Carimune, Glebogamma, Gammagard, Gammaked, Gammar, Gamunex, Hizentra, Iveegam, Octogam, Panglobin, Polygam, Privigen) of parenteral immune globulin are more costly than the alternative least cost brand of parenteral immune globulin that is at least as likely to produce equivalent therapeutic results as to the treatment of the member's disease, under some Aetna plans, other brands of parenteral immune globulin will be considered not medically necessary unless the member has a contraindication or intolerance to the least cost brand of parenteral immune globulin.  If the least cost brand of parenteral immune globulin does not have the labeled indication (see appendix), then Aetna considers medically necessary another brand of parenteral immune globulin that has the required labeling indication.

Notes: The following criteria are considered in assessing the medical necessity of IVIG for the indications listed above.

  1. Clinical monitoring takes clear precedence over laboratory monitoring.  If clinical improvement is evident, then laboratory monitoring solely to guide IVIG therapy is not considered medically necessary.
  2. In some situations, IVIG may be used for medically necessary indications listed above for a person that has rapidly progressive disease in which a clinical response could not be effected quickly enough using conventional agents.  In these situations, IVIG therapy would be given along with conventional treatment(s) and continued administration of IVIG is not considered medically necessary once conventional therapy takes effect.
  3. Once treatment is initiated, there must be adequate documentation of progress.  If there is initial improvement, and continued treatment is necessary, then some type of objective quantitative assessment to monitor the progress is required.  Any accepted metric assessment may be used for objective monitoring of progress, such as the Inflammatory Neuropathy Cause and Treatment (INCAT) scale*, the Medical Research Council (MRC) scale ** and activities of daily living (ADL) measurements.  Changes in these measures should be clearly documented.  Subjective or experiential improvement alone is generally insufficient to either continue IVIG or to expect coverage.
  4. Previous treatment failures must be documented.
  5. The diagnosis of the disorder must be reasonably certain, and based on a thorough history and examination, and appropriate laboratory testing (e.g., electromyography (EMG), spinal fluid tests, serum tests and biopsy findings).
  6. There should be, depending on the diagnosis and clinical circumstances, an attempt made to decrease/wean the dosage when improvement has occurred.  There should be, when clinically appropriate for the diagnosis, an attempt to stop the IVIG infusion if improvement is sustained with dosage reduction.  If improvement does not occur with IVIG, continued infusion may not be considered medically necessary.

* The Inflammatory Neuropathy Cause and Treatment (INCAT) scale is used to access functional disability of both upper and lower extremity components in chronic inflammatory demyelinating polyneuropathy (CIDP).  The INCAT scale has upper and lower extremity components, with a maximum of 5 points for the upper extremity (arm disability) and a maximum of 5 points for the lower extremity (leg disability), which add up to a maximum of 10 points (where 0 is normal and 10 is severely incapacitated).  The INCAT scores may be used to evaluate the effectiveness and need for IVIG.   IVIG may be discontinued when there is a lack of clear clinical improvement (i.e., a decline in INCAT disability score or failure to improve by 1 point at 6 weeks following the initial infusion or return to baseline at anytime following initial improvement of 1 point).

** The Medical Research Council (MRC) scale is used to grade muscle strength.  Scale: 0 = no muscle movement; 1 = flicker of muscle movement; 2 = trace movement but not able to fully overcome gravity; 3 = just able to overcome gravity, but not against resistance; 4 = moves against resistance, but weak; 5 = full strength against resistance.

For IVIG for rubella (German measles), see  CPB 0544 - Immune Globulins for Post-exposure Prophylaxis.



Background

This policy is consistent with guidelines on the use of immunoglobulin therapy from the Centers for Disease Control and Prevention (1999), and the United States Pharmacopeial Convention (2007).

Intravenous immunoglobulin (IVIG) has been shown to be ineffective for the prophylaxis of, and as a treatment adjunct in, infections in some high-risk, preterm, low-birth-weight neonates (USPDI, 2002).  Studies published before 1990 suggested that prophylactic IVIG reduced nosocomial infections in low-birth-weight infants.  However, these studies enrolled small numbers of patients; employed varied designs, preparations, and doses; and included diverse study populations.  The National Institute of Child Health and Human Development (NICHHD) Neonatal Research Network therefore performed a prospective, multi-center, randomized trial to test the hypothesis that the intravenous administration of immune globulin to infants with birth weights between 501 and 1,500 grams would reduce the incidence of nosocomial infections (Fanaroff et al, 1994).  In this trial, the repeated prophylactic administration of IVIG failed to reduce the incidence of nosocomial infections significantly in premature infants weighing 501 to 1,500 grams at birth.  Furthermore, there were no significant differences in morbidity, mortality, or the duration of hospitalization between infants given IVIG and infants given no infusion or an infusion and placebo.

For a discussion of IVIG for recurrent spontaneous abortion, see CPB 0348 - Recurrent Pregnancy Loss.

Several brands of IVIG have been approved by the Food and Drug Adminsitration (FDA) (see table in Appendix).  There is a lack of reliable evidence that any one brand of IVIG is more effective than other brands.  However, immune globulin products may differ from each other in ways that may be important in a particular patient.  Different manufacturers then use various combinations of precipitation and/or chromatography steps to obtain a final preparation that consists of greater than 95 % IgG in all currently available products.  The various manufacturers also use different final purification steps and stabilizers to obtain their final products, which may then vary in storage requirement and shelf life.  In several currently available products, stabilizers include sugars, such as sucrose, glucose, or maltose.  Other products contain amino acids such as glycine and proline.  The sodium content of different products also varies.

Most products approximate the distribution of IgG subclasses found in normal plasma.  However, products are neither standardized nor routinely tested for their content of specific antibodies against different pathogens, except for measles, poliovirus, and hepatitis B surface antigen.

Thus, product-to-product and lot-to-lot variation in specific antibody titers is likely.  There are also product-to-product and lot-to-lot variations in adverse effects in individual patients.  Thus, generic substitution is not acceptable for many patients.  In contrast, the different preparations are generally assumed to have overall equivalent therapeutic efficacy in protecting antibody deficient patients against infection.

Specific patients may require, or do better with, IGIV products with certain characteristics.  Most patients tolerate most products with a minimum of adverse events, or with simple premedications.  Thus, for many patients, selection of a product to conform with local dispensing or formulary preferences may not pose problems.  However, some patients experience a different range and/or severity of adverse effects from different products, which may be impossible to predict.

If a patient is having adverse effects that interfere with IgG replacement, different products should be tried in the hope of finding a product that will be more acceptable.  However, adverse effects may be more frequent and/or more severe whenever a patient is first started on IGIV and whenever a new product is used.  For this reason, extra caution should be used when starting a naïve patient or changing the specific product used by any individual patient.

Some patients require products low in IgA, or products with relatively lower osmolarity, sucrose, or sodium.  Patients with diabetes who use certain types of glucose meters must use caution with maltose-containing products, since that sugar may give false readings for glucose.  Some preparations may have as much as 30 mg/ml (3 %) albumin, in addition to the IgG itself.  This may be undesirable in patients who might have trouble tolerating increased intravascular volume.

The first type of IgG preparation to be used for antibody replacement, 16 % Immune Serum Globulin (ISG) for intra-muscular (IM) administration is still available.  However, the IM route is rarely used at the present time because the injections are painful, the amount given is limited by the volumes that can be administered, and there is risk of local injury, such as nerve damage.

Immune globulin may also been given by the subcutaneous route.  Vivaglobin is an immune globulin [human] subcutaneous injection administered via a small, portable pump for the prevention of serious infection in children and adults with primary immunodeficiency.  Many patients can be readily taught to infuse themselves at home, or parents may administer the infusions to their children.

In April 2006, the American Academy of Asthma, Allergy and Immunology (Orange et al, 2006) published evidence based guidelines on indications for intravenous immunoglobulins.

Darabi et al (2006) noted that IVIG has been approved by the FDA for use in 6 conditions: (i) immune thrombocytopenic purpura (ITP), (ii) primary immunodeficiency, (iii) secondary immunodeficiency, (iv) pediatric HIV infection, (v) Kawasaki disease, and (vi) prevention of graft-versus-host disease (GVHD) and infection in bone marrow transplant recipients.  IVIG has subsequently been approved by the FDA for chronic inflammatory demyelinating polyneuropathy (CIDP).  However, most usage of IVIG is for off-label indications, and for some of these comprehensive guidelines have been published.  Common off-labeled uses for IVIG include chronic neuropathy (e.g., multi-focal motor neuropathy), hypogammaglobulinemia, renal transplant rejection, myasthenia gravis, Guillain-Barre syndrome, necrotizing fasciitis, and autoimmune hemolytic anemia.  The authors concluded that only a few indications account for most of the usage for IVIG.  Reports concerning IVIG continue to grow at a tremendous pace but few high-quality randomized controlled studies have been reported. 

In a review on autism, Levy et al (2009) stated that popular biologically based treatments include anti-infectives, chelation medications, gastrointestinal medications, hyperbaric oxygen therapy, and IVIGs.  Non-biologically based treatments include auditory integration therapy, chiropractic therapy, cranio-sacral manipulation, interactive metronome, and transcranial stimulation.  However, few studies have addressed the safety and effectiveness of most of these treatments.

Whitington and Kelly (2008) stated that neonatal hemochromatosis (NH) is the result of severe fetal liver injury that seems to result from maternal-fetal alloimmunity.  Women who have had an infant affected with NH are at high-risk in subsequent pregnancies for having another affected infant.  This study was designed to examine if therapy directed at limiting the severity of gestational alloimmunity can reduce the occurrence of severe NH in infants of women at risk.  A secondary objective was to use a prospectively collected data set to examine questions of vital interest about NH.  Women with a history of pregnancy ending in documented NH were treated with IVIG at 1 g/kg of body weight weekly from the 18th week until the end of gestation.  Extensive data were prospectively collected regarding the gestational histories of the subjects.  The outcomes of treated pregnancies were compared with those of previous affected pregnancies, which were used as historical controls.  A total of 48 women were enrolled to be treated during 53 pregnancies.  The gestational histories of these women demonstrated the high-risk of occurrence of NH: 92 % of pregnancies at risk resulted in intrauterine fetal demise, neonatal death, or liver failure necessitating transplant.  In contrast, with gestational therapy, the 53 at-risk gestations resulted in 3 failures and 52 infants who survived intact with medical therapy alone.  When compared on a per-woman or per-infant basis, the outcome of gestation at risk for NH was improved by gestational therapy.  The authors concluded that NH seems to be the result of a gestational alloimmune disease, and occurrence of severe NH in at-risk pregnancies can be significantly reduced by treatment with high-dose IVIG during gestation.

In this regard, the Australian National Blood Authority (Gibson et al, 2007) listed NH as one of the conditions for which IVIG has an established therapeutic role.  According to the Australian agency, women who are pregnant or attempting to conceive and their most recent pregnancy ended in delivery of a fetus shown to have had NH are qualified for IVIG therapy.  Dosage should be 1g/kg body weight weekly from the 18th week until the end of gestation.

Anderson et al (2007) noted that to help ensure IVIG use is in keeping with an evidence-based approach to the practice of medicine, the National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for hematologic conditions.  The mandate of the expert panel was to review evidence regarding use of IVIG for 18 hematologic conditions and formulate recommendations on IVIG use for each.  A panel of 13 clinical experts and 1 expert in practice guideline development met to review the evidence and reach consensus on the recommendations for the use of IVIG.  The primary sources used by the panel were 3 recent evidence-based reviews.  Recommendations were based on interpretation of the available evidence and where evidence was lacking, consensus of expert clinical opinion. A draft of the practice guideline was circulated to hematologists in Canada for feedback.  The results of this process were reviewed by the expert panel, and modifications to the draft guideline were made where appropriate.  This practice guideline provided the NAC with a basis for making recommendations to provincial and territorial health ministries regarding IVIG use management.  Specific recommendations for routine use of IVIG were made for 7 conditions including acquired red cell aplasia; acquired hypogammaglobulinemia (secondary to malignancy); fetal-neonatal alloimmune thrombocytopenia; hemolytic disease of the newborn; HIV-associated thrombocytopenia; idiopathic thrombocytopenic purpura; and post-transfusion purpura.  Intravenous immune globulin was not recommended for use, except under certain life-threatening circumstances, for 8 conditions including acquired hemophilia; acquired von Willebrand disease; autoimmune hemolytic anemia; autoimmune neutropenia; hemolytic transfusion reaction; hemolytic transfusion reaction associated with sickle cell disease; hemolytic uremic syndrome/thrombotic thrombocytopenic purpura; and viral-associated hemophagocytic syndrome.  Intravenous immune globulin was not recommended for 2 conditions (aplastic anemia and hematopoietic stem cell transplantation) and was contraindicated for 1 condition (heparin-induced thrombocytopenia).  For most hematologic conditions reviewed by the expert panel, routine use of IVIG was not recommended.

Goebel et al (2010) evaluated the effectiveness of IVIG in patients with longstanding complex regional pain syndrome (CRPS) under randomized, controlled conditions.  Patients who had pain intensity greater than 4 on an 11-point (0 to 10) numerical rating scale and had CRPS for 6 to 30 months that was refractory to standard treatment were enrolled in this study.  Subjects received IVIG (0.5 g/kg) and normal saline in separate treatments, divided by a washout period of at least 28 days.  The primary outcome was pain intensity 6 to 19 days after the initial treatment and the cross-over treatment.  A total of 13 eligible participants were randomly assigned and 12 completed the trial.  The average pain intensity was 1.55 units lower after IVIG treatment than after saline (95 % confidence interval [CI]: 1.29 to 1.82; p < 0.001).  In 3 patients, pain intensity after IVIG was less than after saline by 50 % or more.  No serious adverse reactions were reported.  The drawbacks of this study were that the trial was small, and recruitment bias and chance variation could have influenced results and their interpretation.  The authors concluded that IVIG (0.5 g/kg) can reduce pain in refractory CRPS.  They stated that confirmatory trials are required to ascertain the best immunoglobulin dose, the duration of effect, the need for repeat treatment, and whether treatment response varies with disease duration.

Diabetic amyotrophy usually occurs in patients with poorly controlled diabetes, either as an initial presentation or in a patient with longstanding disease.  The mechanism of diabetic amyotrophy is uncertain, although peri-vascular inflammation and secondary nerve infarction are thought responsible.  A recent consensus statement from the American Academy of Neurology (AAN) concluded that there is "no convincing data" to substantiate the treatment of diabetic amyotrophy using IVIG (Donofrio et al, 2009).

O'Horo and Safdar (2009) stated that clostridium difficile (C. difficile) is the most common infectious cause of nosocomial healthcare-associated diarrhea.  The increasing prevalence of C difficile, spread in the community, virulence and frequent relapse has created an urgent need to identify new effective treatments for C. difficile infection.  Among these, IVIG is used for cases of severe C. difficile infection.  These investigators undertook a systematic review to examine the published literature pertaining to the use of immunoglobulin for C. difficile infection.  Four retrospective studies and 5 case reports that addressed the use of IVIG for the treatment of C. difficile infection were identified.  One study on the use of oral immunoglobulin was identified.  Although overall there appear to be benefits to using IVIG in recurrent severe disease, the small sample sizes and lack of control groups in 3 of the 4 studies do not allow recommendations to be made regarding the use of immunoglobulin in C. difficile infection.  The authors stated that further research is urgently needed to clarify the role of immunoglobulin -- intravenous or oral -- for the treatment of C. difficile infection.

Abougergi et al (2010) stated that C. difficile colitis (CDC) is the most common cause of hospital-acquired diarrhea.  The increase in the incidence and fatality rate of CDC over the past decade has stimulated a search for new therapies, including IVIG.  These researchers reported their experience with IVIG for the treatment of 21 patients with severe CDC.  The existing literature on IVIG infusion for severe CDC was also reviewed.  Twenty-one of 1,230 patients with CDC were treated with IVIG.  The mean age was 68 (range of 35 to 98) years, with mean hospital stay of 23 (range of 9 to 64) days.  Conventional treatment was used for an average of 8 (range of 1 to 25) days before IVIG infusion.  All patients had evidence of pancolitis (radiologically) or ileus (clinically).  The mean Acute Physiological Assessment and Chronic Health Evaluation (APACHE II) score was 25 (range of 6 to 39) at day 1 of IVIG infusion.  Nine patients (43 %) survived their hospitalization with colitis resolution while 12 (57 %) died.  One patient developed pulmonary edema after IVIG infusion.  Symptoms resolved after an average of 10 (range of 2 to 20) days for survivors.  Two patients underwent urgent colectomy.  The authors concluded that this is the largest case series describing IVIG use for patients with severe CDC and the one with the highest mortality rate to date.  The use of IVIG in this setting does not seem to benefit all patients.  Benefit appears to depend on the extent of systemic involvement.  They stated that further studies are needed before adopting IVIG as routine treatment for severe CDC.

Diaz-Manera and colleagues (2009) noted that advances in the treatment of myasthenia gravis (MG) have reduced mortality rates due to the disease and improved patients' quality of life.  Nowadays, attending neurologists can choose among different treatment strategies for MG patients.  An exhaustive revision of published data on the efficacy of the different therapeutic options for MG indicates that there are insufficient evidence-based results.  However, recommendations based on expert opinion can be provided.  Thymectomy is indicated in all patients with a thymoma or for generalized acetylcholine receptor-sero-positive patients aged 18 to 55 years.  Steroids are the most widely used immunosuppressive drug for MG.  They are recommended as the first-line drug in all patients with generalized MG without response to thymectomy, or in those patients who do not fulfill criteria for the surgery.  The selection of second-line drugs may vary between protocols.  The authors recommended starting with azathioprine if insufficient remission is achieved with steroids, followed by ciclosporin, mycophenolate and others.  They use rituximab or cyclophosphamide only in severely drug-resistant patients.  Finally, the authors recommend IVIG or plasma exchange (PE) in MG crisis, or for unstable patients before thymectomy or in clinical exacerbations.

Tranchant (2009) stated that the purpose of the treatment of MG is to improve neuromuscular transmission, and to reduce the production or presence of the nicotinic acetylcholine receptor (achR).  Acetylcholinesterase inhibitors are the first line treatment with the rapid onset of effect, for all types of MG (ocular, generalized MG, sero-negative or sero-positive patients).  Plasmapheresis or IVIG is the treatment for exacerbations.  Their main advantage is the rapid onset of the effect; 3 to 5 PE or IVIG infusions (1.2 to 2 g/body weight administered over 2 to 5 days) are usually recommended.  In case of suspected thymoma, thymectomy should be always performed.  The option of thymectomy was discussed in young patients less than 50 years old with unstable MG, even if thymoma lesions are not suspected.  Corticosteroids and/or immunosuppressive agents are used in severe forms of the disease.  A few randomized studies have shown the effectiveness of the therapeutic agents.  Corticosteroids are considered a major treatment of MG but the doses and periods of time are still being debated.  The combination of corticosteroids and immunosuppressive agents are recommended early to spare corticosteroids.  The treatment of MG should be modulated regularly (minimal doses for example).  The use of IVIG prior to thymectomy was not discussed.

The European Federation of Neurological Societies' task force on the use of IVIG in treatment of neurological diseases (Elovaara et al, 2008) stated that IVIG is an effective treatment for acute exacerbations of MG and for short-term treatment of severe MG (level A); and IVIG is similar to PE regarding effect.  This treatment is safe also for children, during pregnancy, and for elderly patients with complicating disorders.  There is not sufficient evidence to recommend IVIG for chronic maintenance therapy in MG alone or in combination with other immunoactive drugs.  Furthermore, the use of IVIG before thymectomy was not discussed.

Morozumi and associates (2009) evaluated the effect of IVIG therapy in the treatment of neuropathic pain associated with Sjogren's syndrome.  These investigators examined 5 patients affected by painful sensory neuropathy associated with Sjögren's syndrome.  All patients were treated with IVIG (0.4 g/kg/day for 5 days) and pain rating was assessed by the visual analog scale (VAS).  All 5 patients showed a remarkable improvement in neuropathic pain following IVIG therapy.  Pain, assessed by the determination of mean VAS score, was reduced by 73.4 % from days 2 to 14 following treatment.  The observed clinical improvement persisted for 2 to 6 months.  One patient, examined by quantitative sensory testing, showed an improvement of superficial sensory deficit accompanied by pain relief.  The authors concluded that IVIG might be an effective treatment for pain in Sjögren's syndrome-associated neuropathy.  They stated that further studies should be done in a controlled, blind study.

Ishii et al (1994) examined the clinical effects of PE and high dose IVIG in a 41-year old woman with Isaacs' syndrome.  After double filtration PE, symptoms almost disappeared for 2 to 3 weeks and the recorded continuous muscle action potentials were considerably decreased.  Symptoms recurred within a few months.  On the other hand, IVIG worsened the symptoms of the disorder: during and after IVIG at a dose of 0.2 g/kg/day (total 50 g), widespread myokymia, pseudomyotonia, and muscle cramps gradually increased.  Symptoms improved after another course of PE.

Myers and Baker (2009) noted that acquired neuromyotonia, also known as Isaacs' syndrome, has been described in combination with a variety of other autoimmune disorders; however there has never been a report of sero-positive Isaacs' syndrome in a patient with a history of Guillain-Barre syndrome (GBS).  Both conditions involve antibody-mediated autoimmune effects on the peripheral nervous system, although the clinical manifestations are quite different.  These researchers presented a man who experienced an episode of GBS at the age of 21 and subsequently developed Isaacs' syndrome at the age of 24 which was positive for anti-voltage-gated potassium channel (VGKC) antibodies.  When treated with IVIG, he developed an eczematous rash that differed markedly in pattern and duration from the usual presentation for this IVIG reaction.

Aries and colleagues (2005) stated that initially IVIGs were used as replacement therapy in primary and secondary antibody-deficiency syndromes.  The clinical use of IVIG has been extended during the past decade to a wide variety of clinical conditions, such as infectious processes, neuroimmunological diseases, and different systemic autoimmune diseases.  The mode of action of IVIG is complex, involving modulation of the Fc receptors, interference with the complement and cytokine network, and effects on the activation and differentiation of T and B-cells. Kawasaki disease (KD) was one of the first diseases within the group of primary vasculitides in which IVIG were used.  Today, there is a clear evidence of benefit for IVIG in the treatment of coronary artery abnormalities related to KD.  Subsequently, various reports have suggested a beneficial effect in other vasculitides; however, there are few data from controlled studies.  For anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), 1 placebo-controlled and several open-label studies have shown a beneficial effect on the disease activity in patients with Wegener's granulomatosis or microscopic polyangiitis refractory to standard therapy with prednisone and cyclophosphamide.  For other vasculitides, such as polyarteritis nodosa or Henoch-Schonlein purpura, only case reports have described an inhibition of a disease progression by IVIG so far.  However, the effect was partly only temporary.  The authors concluded that KD and AAV are the only vasculitides with a definite beneficial use of IVIG.  For other vasculitides, the efficacy of IVIG has not been proven properly but may be useful in single cases.

Eleftheriou and Brogan (2009) stated that primary systemic vasculitides of the young are relatively rare diseases, but can have a significant morbidity and mortality.  The purpose of this review was to provide an overview of the pediatric vasculitides.  Vasculitides that predominantly affect children will be considered in more detail than vasculitic diseases that although are seen in children affect adults more commonly, such as the ANCA associated vasculitides.  New classification criteria for childhood vasculitis have recently been proposed and are currently undergoing validation.  Epidemiological clues continue to implicate infectious triggers in KD and Henoch Schönlein purpura.  Several genetic polymorphisms have now been described in the vasculitides that may be relevant in terms of disease predisposition or development of disease complications.  Treatment regimens continue to improve, with the use of different immunosuppressive medications and newer therapeutic approaches such as biologic agents.  However new challenges are looming in regards to the role of inflammation in endothelial health and the long term cardiovascular morbidity for children with primary systemic vasculitis.  International multi-center collaboration is of utmost importance in order for us to further advance the understanding and improve the treatment and outcome of systemic vasculitis in the young.  Furthermore, an UpToDate review on "Management of Henoch-Schönlein purpura" (Dedeoglu et al, 2010) did not mention the use of IVIG as a therapeutic option.

Ishii and associates (2010) stated that treatment of autoimmune bullous skin diseases can often be challenging and primarily consists of systemic corticosteroids and a variety of immunosuppressants.  Current treatment strategies are effective in most cases but hampered by the side effects of long-term immunosuppressive treatment. I ntravenous immunoglobulin is one potential promising therapy for patients with autoimmune bullous skin diseases, and evidence of its effectiveness and safety is increasing.  A number of autoimmune bullous skin diseases have been identified in which IVIG treatment may be beneficial.  However, experience with IVIG in patients with autoimmune skin blistering disease is limited, where it is recommended for patients not responding to conventional therapy.  The mode of action of IVIG in autoimmune diseases, including bullous diseases is far from being completely understood.  These researchers summarized the clinical evidence supporting the notion, that IVIG is a promising therapeutic agent for the treatment of patients with autoimmune bullous skin disease.  In addition, they reviewed the proposed modes of action.  In the future, randomized controlled trials are necessary to better determine the efficacy and adverse effects of IVIG in the treatment of autoimmune bullous skin diseases.

Jolles (2011) noted that high-dose IVIG (hdIVIG) is being used increasingly for dermatological indications.  Its mode of action is via a number of proposed mechanisms and it is not associated with the many side-effects of steroids and other immunosuppressive agents.  The evidence for using hdIVIG in the treatment of autoimmune bullous disorders is based on uncontrolled trials and case reports.  However, there are now 62 reported patients and this review aimed to make a critical assessment of the current data.  This has been obtained from a Medline search of the English literature from 1966 to 2000 for pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, pemphigoid gestationis, cicatricial pemphigoid, epidermolysis bullosa acquisita and linear IgA disease.  Taken together hdIVIG was effective in 81 % of the patients with blistering disease.  Patients appear to be more likely to respond when hdIVIG is used as adjunctive therapy (91 % response rate) than as monotherapy (56 % response rate).  The authors concluded that hdIVIG may offer a safe potential therapeutic avenue for resistant cases of the autoimmune bullous disorders but should be further assessed using double-blind placebo-controlled trials.

Parambil et al (2011) stated that small fiber neuropathy (SFN) is commonly associated with sarcoidosis and can cause significant morbidity to afflicted patients.  The appropriate treatment of this condition, when associated with sarcoidosis, is not well established.  These investigators described case series of 3 patients with sarcoidosis and SFN; the presenting clinical features, skin biopsy results, autonomic reflex screen and quantitative sudomotor axon reflex testing (QSART) findings, and response to therapy were delineated.  They described 3 patients with biopsy-proven sarcoidosis who developed intractable neuropathic pain and/or symptoms related to associated autonomic dysfunction despite treatment with various immunosuppressive medications and narcotic analgesics.  QSART showed evidence of a post-ganglionic sudomotor abnormality in 1 patient and was normal in the other 2.  Skin biopsy findings were abnormal, demonstrating a non-length-dependent sensory SFN in all 3 patients.  Painful neuropathic symptoms, as well as symptoms related to dysautonomia from SFN responded significantly to treatment with IVIG.  The authors concluded that IVIG appears to be effective in relieving symptoms from SFN associated with sarcoidosis, suggesting an underlying immune mechanism.  Moreover, they stated that larger prospective, controlled studies are needed to confirm this response to IVIG and to further elucidate the underlying pathobiology behind this association with sarcoidosis.

Isobe et al (2004) described the case of a 40-year old female diagnosed with follicular lymphoma who was treated with rituximab-combined chemotherapy.  Although she achieved complete remission, she developed progressive anemia and reticulocytopenia.  Bone marrow examination revealed features of pure red cell aplasia and hemophagocytosis.  In addition, the appearance of large pronormoblasts suggested that she was infected with parvovirus B19.  Excess viral DNA in her bone marrow confirmed that her illness was caused by persistent parvovirus B19 infection.  Serum immunoglobulin levels decreased beyond the lower normal limit, which indicated that her humoral immunity was impaired after rituximab-combined chemotherapy.  Although she had been infected with parvovirus B19, she was re-infected and failed to control the viral expansion.  High-titer immunoglobulin against parvovirus B19 was intravenously administrated and resulted in remarkable reticulocytosis and improvement of anemia.  High-titer immunoglobulin, which contained a sufficient amount of neutralizing antibodies against parvovirus B19, likely inactivated most viruses in vivo.  These investigators successfully eradicated the virus after 2 courses of high-dose therapy at 0.5 g/kg/day every week followed by 8 courses of maintenance therapy at 0.1 g/kg/day every other week.  It is important to consider that parvovirus B19 infection is a possible cause of progressive anemia in B-cell lymphoma patients treated with rituximab-combined chemotherapy.  The authors proposed that the use of high-titer immunoglobulin against parvovirus B19 may enable such immunocompromised patients to eradicate the virus before sufficient immune system reconstruction.  Also, UpToDate reviews on "Initial treatment of follicular lymphoma" (Freedman and Friedberg, 2011) and "Treatment of relapsed or refractory follicular lymphoma" (Freedman and Friedberg, 2011) do not mention the use of IVIG.

Perlmutter et al (1999) examined if plasma exchange or IVIG would be better than placebo (sham IVIG) in reducing severity of neuropsychiatric symptoms in children, exacerbations of tics and obsessive symptoms.  Children with severe, infection-triggered exacerbations of obsessive-compulsive disorder (OCD) or tic disorders, including Tourette syndrome, were randomly assigned treatment with plasma exchange (5 single-volume exchanges over 2 weeks), IVIG (1 g/kg daily on 2 consecutive days), or placebo (saline solution given in the same manner as IVIG).  Symptom severity was rated at baseline, and at 1 month and 12 months after treatment by use of standard assessment scales for OCD, tics, anxiety, depression, and global function.  A total of 30 children entered the study and 29 completed the trial.  Ten received plasma exchange, 9 IVIG, and 10 placebo.  At 1 month, the IVIG and plasma exchange groups showed striking improvements in obsessive-compulsive symptoms (mean improvement on children's Yale-Brown obsessive compulsive scale score of 12 [45 %] and 13 [58 %], respectively), anxiety (2.1 [31 %] and 3.0 [47 %] improvement on National Institute of Mental Health anxiety scale), and overall functioning (2.9 [33 %] and 2.8 [35 %] improvement on National Institute of Mental Health global scale).  Tic symptoms were also significantly improved by plasma exchange (mean change on Tourette syndrome unified rating scale of 49 %).  Treatment gains were maintained at 1 year, with 14 (82 %) of 17 children "much" or "very much" improved over baseline (7 of 8 for plasma exchange, 7 of 9 for IVIG).  The authors concluded that plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection-triggered OCD and tic disorders.  They stated that further studies are needed to determine the active mechanism of these interventions, and to determine which children with OCD and tic disorders will benefit from immunomodulatory therapies.

In a double-blind placebo-controlled study, Hoekstra et al (2004) studied the effects of IVIG on tics.  A total of 30 patients with a DSM-IV tic disorder were randomly assigned to IVIG (1 g/kg on 2 consecutive days; mean age = 28.71 years; range of 14 to 53 years) or placebo (mean age = 30.73 years; range of 14 to 63 years).  Symptoms were rated with the Yale Global Tic Severity Scale, the Yale-Brown Obsessive Compulsive Scale, and the Clinical Global Impressions scale of symptom change with regard to tic severity.  These were used at baseline and on weeks 2, 4, 6, 10, and 14 post-treatment, after which blinding was broken.  The study was conducted from March through August 2002.  These researchers observed no significant differences between both treatment groups regarding post-treatment changes in tic severity.  Severity of obsessions and compulsions, which was in the subclinical range, decreased significantly in the IVIG group compared with the placebo group at week 6 (p = 0.02).  Then, there was a 32.3 % improvement in the IVIG group compared with baseline.  Though this improvement was maintained over the following 8 weeks, no statistically significant differences between the IVIG and the placebo group with regard to improvements in obsessions and compulsions were detected at subsequent assessments.  IVIG treatment was associated with significantly more side effects than placebo, most notably headache.  The authors concluded that based on the present results, IVIG can not be recommended in tic disorders.

Trucco et al (2011) evaluated the outcome of maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis following IVIG and corticosteroid therapy.  These researchers have previously shown that 85 % of fetuses and infants with maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis suffer demise or need for transplant.  In an attempt to improve this outcome, in 1998, they began to empirically treat affected patients with IVIG and corticosteroids.  These investigators reviewed the clinical records and echocardiograms of 20 affected patients encountered in their institutions and treated with IVIG and corticosteroids from 1998 to 2009.  All 20 were initially referred at a median gestational age of 23 weeks (range of 18 to 38 weeks); 19 mothers were anti-Ro antibody positive, 8 anti-La antibody positive, and 7 had clinical autoimmune disease.  Endocardial fibroelastosis was seen in 16 and was not obvious in 4 others with reduced ventricular function, and 16 (80 %) had reduced or borderline ventricular shortening fraction (less than or equal to 30 %) before or after birth.  Eighteen had atrioventricular block at referral (16 in 3°).  During pregnancy, maternal IVIG was given in 9 and dexamethasone in 17.  After birth, 17 infants received IVIG (n = 14) and/or corticosteroids (n = 15).  Twelve underwent pacemaker implantation.  Four with hydrops at presentation died perinatally, despite initial improvement in function in 3.  At a median follow-up of 2.9 years (1.1 to 9.8 years), 16 (80 %) patients are currently alive with normal systolic ventricular function and 6 are not paced.  The authors concluded that treatment of maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis with IVIG and corticosteroids potentially improves the outcome of affected fetuses.  They stated that further studies (prospective, multi-center randomized trials including the evaluation of maternal and neonatal titers before and after therapy) are needed to determine the optimal dose and timing of IVIG administration. 

In a Cochrane review, Ohlsson et al (2010) evaluated the effect of IVIG on mortality/morbidity caused by suspected infection in neonates and in those neonates who had suspected infection on study entry and later were confirmed as being infected.  These investigators searched MEDLINE, EMBASE, The Cochrane Library, the reference lists of identified studies, meta-analyses and personal files in December 2009.  They selected randomized or quasi-randomized controlled trials of IVIG for the treatment of suspected bacterial/fungal infection compared to placebo or no intervention in newborn infants (less than 28 days old).  Statistical analyses included Typical Relative Risk (RR), Risk Difference (RD), weighted mean difference (WMD), the number needed to treat to benefit (NNTB) (all with with 95 % CI and the I(2) statistic to examine statistical heterogeneity.  The updated search identified 1 new study; 10 studies of variable quality undertaken in 8 countries are included in this review.  Mortality in infants with clinically suspected infection was reduced following IVIG treatment [7 studies (n = 378); typical RR 0.58 (95 % CI: 0.38, 0.89); typical RD -0.10 (95 % CI: - 0.18, -0.03); NNTB 10 (95 % CI: 6, 33); I(2) = 0 %].  Mortality in cases of subsequently proven infection was reduced [7 trials (n = 262); typical RR 0.55 (95 % CI: 0.31, 0.98); I(2) = 0 %].  The authors concluded that because of concerns about study quality, there is still insufficient evidence to support the routine administration of IVIG to prevent mortality in infants with suspected or subsequently proved neonatal infection.  A large study of the effectiveness of IVIG in neonates with suspected infection has recently been completed.  Results of the International Neonatal Immunotherapy Study (INIS trial), which enrolled 3,493 infants, are expected to be published in 2010.  The results of that trial should establish the usefulness of IVIG for suspected infection in newborns.

The INIS Collaborative Group (2011) stated that neonatal sepsis is a major cause of death and complications despite antibiotic treatment.  Effective adjunctive treatments are needed.  Newborn infants are relatively deficient in endogenous immunoglobulin.  Meta-analyses of trials of IVIG for suspected or proven neonatal sepsis suggest a reduced rate of death from any cause, but the trials have been small and have varied in quality.  At 113 hospitals in 9 countries, these investigators enrolled 3,493 infants receiving antibiotics for suspected or proven serious infection and randomly assigned them to receive 2 infusions of either polyvalent IgG immune globulin (at a dose of 500 mg/kg body weight) or matching placebo 48 hours apart.  The primary outcome was death or major disability at the age of 2 years.  There was no significant between-group difference in the rates of the primary outcome, which occurred in 686 of 1,759 infants (39.0 %) who received IVIG and in 677 of 1,734 infants (39.0 %) who received placebo (relative risk, 1.00; 95 % CI: 0.92 to 1.08).  Similarly, there were no significant differences in the rates of secondary outcomes, including the incidence of subsequent sepsis episodes.  In follow-up of 2-year-old infants, there were no significant differences in the rates of major or non-major disability or of adverse events.  The authors concluded that therapy with IVIG had no effect on the outcomes of suspected or proven neonatal sepsis.

Kim and colleagues (2011) stated that the prognosis of MG has improved dramatically due to advances in critical-care medicine and symptomatic treatments.  Its immunopathogenesis is fundamentally a T-cell-dependent autoimmune process resulting from loss of tolerance toward self-antigens in the thymus.  Thymectomy is based on this immunological background.  For MG patients who are inadequately controlled with sufficient symptomatic treatment or fail to achieve remission after thymectomy, remission is usually achieved through the addition of other immunotherapies.  These immunotherapies can be classified into 2 groups: (i) rapid induction and (ii) long-term maintenance.  Rapid induction therapy includes IVIG and PE.  These produce improvement within a few days after initiation, and so are useful for acute exacerbation including myasthenic crisis or in the peri-operative period.  High-dose prednisone has been more universally preferred for remission induction, but it acts more slowly than IVIG and PE, commonly only after a delay of several weeks.  Slow tapering of steroids after a high-dose pulse offers a method of maintaining the state of remission.  However, because of significant side effects, other immunosuppressants (ISs) are frequently added as "steroid-sparing agents".  The currently available ISs exert their immunosuppressive effects by 3 mechanisms: (i) blocking the synthesis of DNA and RNA, (ii) inhibiting T-cell activation and (iii) depleting the B-cell population.  In addition, newer drugs including antisense molecule, tumor necrosis factor alpha receptor blocker and complement inhibitors are currently under investigation to confirm their effectiveness.  Until now, the treatment of MG has been based primarily on experience rather than gold-standard evidence from randomized controlled trials.  It is hoped that well-organized studies and newer experimental trials will lead to improved treatments.

A review of treatment of IgG subclass deficiencies (Lemmon & Knutsen, 2012) explains that, “in patients receiving immune globulin replacement therapy, treatment should periodically be held after one to two years for immunologic and clinical reassessment. When discontinuing immune globulin, it is advisable to do so during the spring months to minimize exposure to viral infections. We generally wait three or four months after discontinuation before performing immune testing.” The authors explain, as a rationale for this reassessment, that some people do not respond to IgG replacement therapy, and also that, especially in younger patients, immune responsiveness and IgG subclass levels may normalize over time.

The American College of Obstetricians and Gynecologists’ practice bulletin on “Antiphospholipid syndrome” (ACOG, 2011) indicated that IVIG was considered but not recommended for pregnant women with APS.

Also, the British Committee for Standards in Haematology’s guidelines on “The investigation and management of antiphospholipid syndrome” (Keeling et al, 2012) does not mention the use of IVIG.

Alijotas-Reig (2013) stated that currently there are no reliable data regarding the actual treatment received by women with refractory obstetric APS (OAPS).  These researchers evaluated current clinical evidence and new trends in the treatment of refractory OAPS.  A non-systematic but comprehensive literature search using relevant keywords was made to identify relevant articles published in English from different computerized databases: PubMed (Medline), Google Scholar electronic database search and The Cochrane Library, from January 2000 to March 2012.  Studies on the treatment of poor obstetric outcomes in women with OAPS were included.  Prospective randomized clinical trials, cohort studies, reviews, systematic reviews and meta-analysis were retrieved.  A total of 130 articles were finally selected for this review, including 17 randomized clinical trials and 4 meta-analyses.  The majority of articles were non-randomized original papers and basic and clinical reviews.  The authors concluded that up to 20 % of women with OAPS do not receive the currently recommended therapeutic regimen.  Unfortunately, well-designed studies regarding the usefulness of new drugs in refractory OAPS are scarce.  Hydroxychloroquine and low-dose prednisolone appear to be useful when added to standard therapy.  Current data do not support the use of IVIG in this field. 

The American Academy of Child and Adolescent Psychiatry’s practice parameter for the assessment and treatment of children and adolescents with obsessive-compulsive disorder (AACAP, 2012) stated that “Therapeutic plasma exchange and intravenous immunoglobulin remain experimental interventions with substantial risk and potential morbidity”.

Also, UpToDate reviews on “Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications” (Krull, 2012a), “Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis” (Krull, 2012b), and “Adult attention deficit hyperactivity disorder” (Searight and Burke, 2012) do NOT mention the use of IVIG as a therapeutic option.

UpToDate reviews on “Initial treatment of depression in adults” (Katon and Ciechanowski, 2012a) and “Treatment of resistant depression in adults” (Katon and Ciechanowski, 2012b) do NOT mention the use of IVIG as a therapeutic option.

An UpToDate review on “The diffuse alveolar hemorrhage syndromes” (Schwarz, 2012) states that “The possible role of intravenous immunoglobulin (IVIG) in patients with DAH due to vasculitis or other connective tissue disease is unknown”.

An UpToDate review on “PANDAS: Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci” (Pichichero, 2012) states that “Routine administration of immunomodulatory therapy (e.g., glucocorticoids, plasma exchange, intravenous immunoglobulin [IVIG]) is not indicated for children who meet PANDAS criteria”.

Perlmutter et al (1999) reported on 29 children who were randomized to one of three groups: plasma exchange (n=10), IVIG (n=9), or placebo (n=10).  They found that at 1 month, the IVIG and plasma-exchange groups showed striking improvements in obsessive-compulsive symptoms (mean improvement on children’s Yale-Brown obsessive compulsive scale score of 12 [45%] and 13 [58%], respectively), anxiety (2·1 [31%] and 3·0 [47%] improvement on National Institute of Mental Health anxiety scale), and overall functioning (2·9 [33%] and 2·8 [35%] improvement on National Institute of Mental Health global scale).  The investigators concluded that plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection triggered OCD and tic disorders. The investigators stated that further studies are needed to determine the active mechanism of these interventions, and to determine which children with OCD and tic disorders will benefit from immunomodulatory therapies. This three armed trial with 10 or less participants per arm has limited statistical power.

Martino et al (2009) stated that despite their empirical use in community settings, there is still a lack of conclusive, evidence-based data regarding the usefulness of antibiotic and immuno-modulatory treatments in children with PANDAS. 

Shulman (2009) noted that the relationship between obsessive-compulsive disorder (OCD) or tics/Tourette's syndrome in childhood to antecedent group A streptococci (GAS) is unclear.  One recent prospective cohort study found that more than 85 % of clinical exacerbations in OCD/tic behavior in patients who met criteria for PANDAS had no relationship to GAS infection.  Another study found no correlation between clinical exacerbations and changes in a variety of markers of brain autoimmunity, the proposed pathogenesis of PANDAS.  A third recent study concluded that, compared with specialty clinic diagnoses, patients diagnosed with tics or Tourette's by physicians in the community were significantly more likely to be diagnosed with PANDAS without meeting the proposed criteria, most lacked supporting laboratory evidence of GAS infection, and they were more likely to be treated with unjustified short-term to chronic antibiotic and/or immuno-modulatory therapy. 

Marconi et al (2009) stated that the use of treatment strategies, such as therapeutic plasmapheresis or IVIG, has been proposed to explain the autoimmune process responsible for the pathogenesis of PANDAS.  Moreover, they stated that further research is still necessary in order to understand the role of streptococcal infection in the pathogenesis of PANDAS.

Tan et al (2012) posed the question “I have heard about children who have tic disorders that seem to be exacerbated by group A β-hemolytic streptococcal infection. Should children presenting with this phenomenon receive treatment with antibiotics, receive prophylactic treatment, or use immunomodulators to treat the symptoms?”  They noted the answer to be: “Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) constitute a condition that includes neuropsychiatric symptoms, mainly obsessive-compulsive disorder or tic disorders, temporally associated with an immune-mediated response to streptococcal infections. The actual existence of PANDAS as a unique clinical entity is still up for debate, as a temporal association between group A β-hemolytic streptococcal infections and symptom exacerbations has been difficult to prove thus far. Based on only a few studies, positive results have been found using antibiotic prophylaxis and immunomodulatory therapy in children with PANDAS. At this time, however, evidence does not support a recommendation for long-term antibiotic prophylaxis or immunomodulatory therapy.”

The AAN’s evidence-based guideline on “Intravenous immunoglobulin in the treatment of neuromuscular disorders” (Patwa et al, 2012) states that IVIG is as efficacious as plasmapheresis and should be offered for treating Guillain-Barré syndrome (GBS) in adults (Level A).  IVIG is effective and should be offered in the long-term treatment of chronic inflammatory demyelinating polyneuropathy (Level A).  IVIG is probably effective and should be considered for treating moderate-to-severe myasthenia gravis and multifocal motor neuropathy (Level B).  IVIG is possibly effective and may be considered for treating non-responsive dermatomyositis in adults and Lambert-Eaton myasthenic syndrome (Level C).  Evidence is insufficient to support or refute use of IVIG in the treatment of immunoglobulin M paraprotein-associated neuropathy, inclusion body myositis, polymyositis, diabetic radiculoplexoneuropathy, or Miller Fisher syndrome, or in the routine treatment of post-polio syndrome or in children with GBS (Level U).  IVIG combined with plasmapheresis should not be considered for treating GBS (Level B).  More data are needed regarding IVIG efficacy as compared with other treatments/treatment combinations. 

Appendix

Condition Indications
Acute disseminated encephalomyelitis IVIG may be considered medically necessary in persons with acute disseminated encephalomyelitis who have an insufficient response to intravenous corticosteroid treatment. 
Autoimmune hemolytic anemia, refractory IVIG may be considered medically necessary in persons with warm-type autoimmune hemolytic anemia that does not respond to corticosteroids or splenectomy, or those for whom the latter two treatments are contraindicated.
Bacterial infection in HIV-infected children

Consistent with recommendations of the Working Group on Antiretroviral Therapy of the National Pediatric HIV Resource Center IVIG is considered medically necessary in children with HIV-infection who meet any of the following criteria:

  1. Those with hypogammaglobulinemia, i.e., serum IgG concentration less than 250 mg/dL;  
  2. Those with recurrent serious bacterial infections, i.e., defined as two or more infections such as bacteremia, meningitis, or pneumonia in a 1-year period;  
  3. Those who fail to form antibodies to common antigens, such as measles, pneumococcal, and/or Haemophilus influenzae type b vaccine;  
  4. Those living in areas where measles is highly prevalent and who have not developed an antibody response after two doses of measles, mumps, and rubella virus vaccine live;  
  5. Single dose for HIV-infected children who are exposed to measles;  
  6. HIV-infected children with chronic bronchiectasis that is suboptimally responsive to antimicrobial and pulmonary therapy.
Birdshort (vitiligenous) retinochoroidopathy IVIG is considered medically necessary for birdshot (vitiligenous) retinochoroidopathy that is not responsive to immunosuppressives (e.g., corticosteroids, cyclosporine).
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), also known as Chronic Relapsing Polyneuropathy, including diabetes mellitus-CIDP and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) variant

Symmetric or focal neurologic deficits with slowly progressive or relapsing course over 2 months or longer (with neurophysiological abnormalities). 

Note:  A meta-analysis comparing the efficacy if IVIG, plasma exchange, and oral glucocorticoids found equivalence between all three, at least within the first 6 weeks of therapy (Van Schaik et al, 2002).  IVIG is considered under accepted guidelines as the preferred treatment, particularly in children, when there is difficulty with venous access for plasmapheresis, and those susceptible to the complications of long-term corticosteroid therapy (Orange et al, 2006).

Persons typically respond to IVIG or plasma exchange within the first several weeks of treatment and may demonstrate sustained improvement for many weeks or months.  Relapses may require periodic isolated treatments with a single dose of IVIG or single plasma exchange.  If a person responds successfully to infrequent booster treatments of either IVIG or plasma exchange, it is considered medically necessary to prescribe maintenance therapy with IVIG to prevent relapse, rather than adding corticosteroids or other immunosuppressants.

Chronic Lymphocytic Leukemia (CLL) in patients with hypogamma-globulinemia

IgG level less than 600 mg/dL; and:

  1. 1 severe bacterial infection within preceding 6 months or 2 or more bacterial infections in 1 year; or  
  2. Evidence of specific antibody deficiency.

Dermatomyositis, Polymyositis(includes Juvenile)

  1. Members presenting at least one item from the 1st criterion and four items from the 2nd through 9th criteria are said to have dermatomyositis.  Patients presenting no items from the 1st criterion and at least four items from the 2nd through 9th criteria are said to have polymyositis.

    1. Skin lesions 

      1. Heliotrope rash (red purple edematous erythema on the upper palpebra) 
      2. Gottron's sign (red purple keratotic, atrophic erythema, or macules on the extensor surface of finger joints) 
      3. Erythema on the extensor surface of extremity joints: slightly raised red purple erythema over elbows or knees 

    2. Proximal muscle weakness (upper or lower extremity and trunk) 
    3. Elevated serum CK (creatine kinase) or aldolase level 
    4. Muscle pain on grasping or spontaneous pain 
    5. Myogenic changes on EMG (short-duration, polyphasic motor unit potentials with spontaneous fibrillation potentials) 
    6. Positive anti-Jo-1 (histadyl tRNA synthetase) antibody 
    7. Non-destructive arthritis or arthralgias 
    8. Systemic inflammatory signs (fever: more than 37° C at axilla, elevated serum CRP level or accelerated ESR of more than 20 mm/h by the Westergren method) 
    9. Pathological findings compatible with inflammatory myositis (inflammatory infiltration of skeletal evidence of active regeneration may be seen

    AND

  2. Member has severe active illness; and

  3. Member is intolerant or refractory to 1st and 2nd line therapies:  

    1. 1st line therapy - Corticosteroids (e.g., prednisone);  
    2. 2nd line therapy - Immuno-suppressants (e.g., methotrexate, azathioprine, cyclophosphamide, and cyclosporine).  
Enteroviral meningoencephalitis IVIG is considered medically necessary in severe cases of enteroviral meningoencephalitis lacking other therapeutic options.
Fetal Alloimmume Thrombocytopenia (FAIT)

Maternal and paternal platelet typing reveals the father has a platelet antigen that the mother lacks and the mother has detectable antibodies to this antigen (to HPA 1a are the most common cause of FAIT); and

  1. At 20 weeks or later, cordocentesis reveals fetal platelets less than 20 x 1000/mL(3); or  
  2. Previous pregnancy affected by FAIT.

Guillain Barre Syndrome (GBS) a.k.a. acute infective polyneuritis (includes GBS variants: Miller-Fisher syndrome [MFS], pan autonomic polyneuropathy, acute pandysautonomia, acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN))

  1. Severe GBS with significant weakness such as inability to stand or walk without aid, respiratory or bulbar weakness, or Miller-Fisher syndrome (MFS); and  
  2. The disorder has been diagnosed during the first 2 weeks of the illness; and  
  3. IVIG is initiated within one month of symptom onset.  Note: Based on the 2003 AAN guidelines, IVIG should usually be initiated within 2 weeks and no longer than 4 weeks of onset of neuropathic symptoms.
Hematopoietic Stem Cell Transplant (HSCT) or Bone Marrow Transplant (BMT) 

IVIG is considered medically necessary for prophylaxis in allogeneic or syngeneic transplant recipients within the first 100 days post-transplant; after 100 days post-transplant IVIG is indicated for treatment of recipients who are markedly hypogammaglobulinemic (IgG level less than 400 mg/dL) or who have CMV, EBV, or RSV infection.

IVIG is considered medically necessary for steroid-resistant graft-versus-host disease in BMT recipients 20 years of age or older, in the first 100 days post transplant, and who are hypogammaglobinemic (IgG level less than 400 mg/dL).

HIV-associated Thrombocytopenia - Adult

  1. Significant bleeding in thrombocytopenic patients or platelet count less than 20,000/ul; and  
  2. Failure of RhIG in Rh-positive patients.

HIV-associated Thrombocytopenia - Pediatric

Infants and children less than 13 years of age whose IgG level is less than 400 mg/dL; and

  1. 2 or more bacterial infections in a 1-year period despite antibiotic chemoprophylaxis with TMP-SMZ or another active agent; or  
  2. Child has received 2 doses of measles vaccine and lives in a region with a high prevalence of measles; or  
  3. Member has HIV-associated thrombocytopenia despite anti-retroviral therapy; or  
  4. Member has chronic bronchiectasis that is suboptimally responsive to antimicrobial and pulmonary therapy; or  
  5. T4 cell count is greater than or equal to 200/mm3.
Hemolytic Disease of the Newborn Not responding to phototherapy to decrease the need for exchange transfusion.  Physician discretion important in deciding.
Hyperimmunoglobulin E Syndrome (Job Syndrome; Hyper IgE syndrome) Recurrent staphylococcal abscesses and markedly elevated serum IgE with normal IgG, IgA, and IgM concentrations.
Idiopathic Thrombocytopenic Purpura (ITP) - Adult
  1. Other causes of thrombocytopenia have been ruled out by history and peripheral smear; and

    Unresponsive to corticosteroid therapy; and

    Management of acute bleeding due to severe thrombocytopenia (platelet counts less than 30,000/ul); or  

  2. To increase platelet counts prior to invasive major surgical procedures (e.g., splenectomy), or  
  3. To defer or avoid splenectomy; or  
  4. In members with severe thrombocytopenia (platelet counts less than 20,000/ul) considered to be at risk for intra-cerebral hemorrhage.
Idiopathic Thrombocytopenic Purpura (ITP) - Pediatric

Acute ITP:

  1. IVIG as initial therapy if platelet count less than 20,000/ul, especially when member has emergency bleeding or is at risk for severe life-threatening bleeding; or  
  2. Persons with severe thrombo-cytopenia (platelet counts less than 20,000/ul) considered to be at risk for intra-cerebral hemorrhage.

Note:  IVIG not indicated if only mild manifestations of bleeding.

Chronic ITP:

In high-risk persons when platelet count low or person symptomatic; and

  1. Failure of other therapies, or  
  2. Member is a high risk for post-splenectomy sepsis.
Idiopathic Thrombocytopenic Purpura (ITP), Chronic Refractory
  1. Age of 10 years or older; and  
  2. Duration of illness of greater than 6 months; and  
  3. No concurrent illness/disease explaining thrombocytopenia; and   
  4. Prior treatment with corticosteroids and splenectomy has failed or member is at high-risk for post-splenectomy sepsis. 
Immune Thrombocytopenic Purpura (ITP) in Pregnancy
  1. Refractory to steroids with platelet counts less than 10,000/ul in the 3rd trimester; or  
  2. Platelet counts less than 30,000/ul associated with bleeding before vaginal delivery or C-section; or  
  3. Pregnant women who have previously delivered infants with autoimmune thrombocytopenia; or  
  4. Pregnant women who have platelet counts less than 50,000/ul during the current pregnancy; or  
  5. Pregnant women with past history of splenectomy.
Immunosuppressed Patients

To prevent or modify recurrent bacterial or viral infections (e.g., CMV) in members with iatrogenically induced, or disease associated immunosuppression (IgG less than 400 mg/dL) with one of the following:

  1. Solid organ transplants or extensive surgery with immunosuppression (Note: In particular, IVIG may be medically necessary in persons undergoing multiple courses of plasmapheresis as a treatment for allograft rejection or for other indications; these persons may receive IVIG at the completion of therapy if their IgG level is less than 400 mg/dL); or
  2. Hematological malignancy; or  
  3. Extensive burns; or  
  4. Collagen-vascular disease.
Kawasaki disease (Mucocutaneous Lymph Node Syndrome [MCLS])

Diagnosis must be established -- no specific lab test -- diagnosis is established by meeting the following criteria:

  1. Fever present for at least 5 days; and  
  2. 4 of the following 5 conditions are met:  

    1. Mucous membrane changes such as a red tongue and dry fissured lips;  
    2. Swelling of the hands and feet;  
    3. Enlarged lymph nodes in the neck;  
    4. Diffuse red rash covering most of the body;  
    5. Redness of the eyes.
Lambert-Eaton Myasthenic Syndrome (LEMS)

No response to anti-cholinesterases and dalfampridine (Ampyra); and

  1. Used as an alternative to plasma exchange if weakness is severe; or  
  2. When there is difficulty with venous access for plasmapheresis. 
Myasthenia Gravis
  1. Treatment of acute myasthenic crisis with decompensation (respiratory failure, or disabling weakness requiring hospital admission); and
  2. Other treatments have been unsuccessful or are contraindicated (e.g., azathioprine, cyclosporine, and cyclophosphamide).

Note: For management of myasthenic crises, IVIG is administered over 2 to 5 days.  Use of IVIG as maintenance therapy is considered experimental and investigational.

Moersch-Woltmann (Stiff-man) Syndrome
  1. Presence of anti-GAD antibody; and  
  2. Benzodiazepines (e.g., Valium) and/or baclofen, phenytoin, clonidine, tizanidine have failed.
Multifocal Motor Neuropathy with Conduction Block Progressive, symptomatic multifocal motor neuropathy that has been diagnosed on the basis of electrophysiologic findings that rule out other possible conditions that may not respond to IVIG treatment.  
Multiple Myeloma (MM)
  1. "Plateau Phase" MM (greater than 3 months since diagnosis); and 
  2. IgG level less than 600 mg/dL; and  
  3. 2 or more significant infections in last year or a single life threatening infection; or 

Evidence of specific antibody deficiency.

Multiple Sclerosis (MS) -  Relapsing-remitting (not primary or secondary progressive MS)

  1. Severe manifestations of relapsing-remitting MS (not primary or secondary progressive MS); and  
  2. Standard approaches (i.e., interferons – Betaseron, Avonex, Rebif) have failed, become intolerable, or are contraindicated.
Neonatal Hemochromatosis  Treatment of pregnant women who have a history of pregnancy ended in documented neonatal hemochromatosis. (Note: Dosage should be 1g/kg body weight weekly from the 18th week until the end of gestation).
Neuroblastoma associated paraneoplastic opsoclonus-myoclonus-ataxia syndrome Treatment of opsoclonus-myoclonus-ataxia associated with neuroblastoma.
Opsoclonus-myoclonus Medically necessary as last-resort treatment for refractory opsoclonus-myoclonus.

Erythrovirus (formerly parvovirus) B19 Infection, Chronic, with Severe Anemia (Pure Red Cell Aplasia)

Severe, refractory anemia with documented erythrovirus B19 viremia.
Autoimmune Mucocutaneous Blistering Diseases - includes Pemphigus vulgaris, Pemphigus foliaceus, Bullous Pemphigoid, Mucous Membrane Pemphigoid (a.k.a. Cicatricial Pemphigoid), and Epidermolysis bullosa aquisita
  1. The diagnosis has been proven by biopsy and confirmed by pathology report; and  
  2. The condition is rapidly progressing, extensive or debilitating; and  
  3. Corticosteroids, immuno-suppressive agents have failed or the member has experienced significant complications from standard treatment, such as diabetes or steroid-induced osteoporosis. 
Post-transfusion purpura (PTP)
  1. Decreased platelets (usually less than 10,000/ul); and 
  2. 2 to 14 days post-transfusion with bleeding.

Primary Humoral Immunodeficiencies

  1. Selective IgM Immunodeficiency  
  2. Congenital hypogamma-globulinemia  
  3. Immunodeficiency with near/normal IgM (absent IgG, IgA) – a.k.a. Hyper IgM syndrome  
  4. Other deficiency of humoral immunity  
  5. Severe combined immunodeficiency disorders (e.g., X-SCID, jak3, ZAP70, ADA, PNP, RAG defects, Ataxia Telangiectasia,  DiGeorge syndrome, common variable immunodeficiency)
  1. Agammaglobulinemia (total IgG less than 200 mg/dL or infants with BTK gene and/or absence of B lymphocytes)); or  
  2. Persistent hypogammaglobulinemia(total IgG less than 400 mg/dL) with recurrent bacterial infections and/or lack of response to protein or polysaccharide antigens (inability to make IgG antibody against diphtheria and tetanus toxoids, pneumococcal polysaccharide vaccine, or both):

    1. Serum antibody titres to tetanus and/or diphtheria should be obtained prior to immunization with diphtheria and/or tetanus vaccine and 3 to 4 weeks after immunization.  An inadequate response is defined as less than a 4-fold rise in antibody titer and lack of protective antibody level (as defined by laboratory performing the assay); and
    2. Serum antibody titers to pneumococcus should be measured prior to immunization and 3 to 6 weeks after immunization with polyvalent pneumococcal polysaccharide vaccine (e.g., Pneumovax).  An inadequate response is defined as less than a 4-fold rise in titer over baseline in at least one serotype tested and lack of protective antibody level (i.e., specific IgG concentration less than 1.3 mcg/ml); or
        
  3. Selective IgG subclass deficiencies (see criteria in section of selective IgG subclass deficiency below); or
  4. Normal total IgG levels with severe polysaccharide non-responsiveness and evidence of recurrent severe difficult-to-treat infections (e.g., recurrent otitis media, bronchiectasis, recurrent infections requiring IV antibiotics, multiple antibiotic hypersensitivities, chronic or recurrent sinusitis) (see table below) with a documented requirement for antibiotic therapy:

    1. Member has unexplained recurrent or persistent severe bacterial infections despite adequate treatment, including all of the following:

      1. Aggressive management of other conditions predisposing to recurrent sinopulmonary infections (e.g., asthma, allergic rhinitis);
      2. Prophylactic antibiotics;
      3. Increased vigilance and appropriate antibiotic therapy for infections; and
      4. Immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines.
         
    2. Serum antibody titers to pneumococcus should be measured prior to immunization and 3 to 6 weeks after immunization with polyvalent pneumococcal polysaccharide vaccine (e.g., Pneumovax); at least 14 polysaccharide antigens should be tested. 
    3. Polysaccharide non-responsiveness is defined as less than 4-fold rise in antibody titer and lack of protective antibody titer (specific IgG antibody titer less than 1.3 mcg/ml) in greater than 30 % of antigens tested (more than 50 % in children aged 2 to 5 years).
    4. Further evidence of infection, including sinus and lung imaging, complete blood counts, C-reactive protein measurement, and erythrocyte sedimentation rate determination, may be required to support the need for IVIG supplementation.
    5. For persons with normal total IgG levels and severe polysaccharide nonresponsiveness, IVIG should be discontinued and the medical necessity of IVIG should be re-evaluated 1 year after initiating therapy and every 2 years thereafter by reassessing immune response to protein and polysaccharide antigens.  Immune response should be re-evaluated at least 3 months after discontinuation of IVIG.  IVIG should also be discontinued at that time if the number and/or severity of infections have not been reduced, as not all persons with polysaccharide nonresponsiveness benefit from IVIG.

The use of IVIG may not be beneficial in certain secondary immunodeficiency states; correction of the underlying condition is the preferred approach.

Rasmussen Encephalitis

For children whose symptoms do not improve with anti-epileptic drugs and corticosteroids.

Selective IgG Subclass Deficiency
  1. Deficiency of one or more IgG subclasses to levels less than 2 standard deviations below the age-specific mean (see table below).  These levels should be assessed on at least two occasions while the patient is free of infections; and
  2. Member has unexplained recurrent or persistent severe bacterial infections despite adequate treatment, including all of the following:

    1. Aggressive management of other conditions predisposing to recurrent sinopulmonary infections (e.g., asthma, allergic rhinitis);
    2. Prophylactic antibiotics;
    3. Increased vigilance and appropriate antibiotic therapy for infections; and
    4. Immunization with conjugate vaccines in patients who have not responded to polysaccharide vaccines; and

  3. Member has demonstrated an inability to mount an adequate response to protein and polysaccharide antigens, as determined by the following criteria:

    1. Member has documented inability to mount an antibody response to protein antigens: Serum antibody titers to tetanus and/or diphtheria should be obtained prior to immunization with diphtheria and/or tetanus vaccine and 3 to 4 weeks after immunization.  An inadequate response is defined as less than a 4-fold rise in antibody titer and lack of protective antibody level (as defined by laboratory performing the assay); and
    2. Member has documented inability to mount an adequate antibody response to polysaccharide antigens.  Serum antibody titres to at least 14 pneumococcus serotypes should be measured prior to immunization and 3 to 6 weeks after immunization with polyvalent pneumococcal polysaccharide vaccine (e.g., Pneumovax).  An inadequate response is defined as less than a 4-fold rise in titer over baseline in at least 30 % of serotypes tested (in at least 50 % of serotypes tested in children aged 2 to 5 years) and lack of protective antibody level (i.e., specific IgG concentration less than 1.3 mcg/ml); and 

    Note: Response to polysaccharide antigens is not reliable in children less than 2 years of age.

  4. IVIG should be discontinued and the medical necessity of IVIG should be re-evaluated 1 year after initiating therapy and every 2 years thereafter by re-assessing immune response to protein and polysaccharide antigens.  Immune response should be re-evaluated at least 3 months after discontinuation of IVIG.  IVIG should also be discontinued at that time if the number and/or severity of infections have not been reduced, as not all persons with selective IgG subclass deficiencies benefit from IVIG. 
Staphylococcal Toxic Shock Syndrome Severe cases of toxic shock syndrome that have not responded to fluids and vasopressors.
Systemic Lupus Erythematosus

Members with severe active SLE for whom 1st- and 2nd-line therapies have been unsuccessful, have become intolerable, or are contraindicated.  

Note: Standard 1st-line therapy of active SLE include non-steroidal anti-inflammatory drugs, followed by low-dose corticosteroids and antimalarial compounds; 2nd-line therapeutic alternatives are the cytotoxic agents methotrexate, azathioprine, or cyclophosphamide.

Toxic epidermal necrolysis and Stevens-Johnson syndrome IVIG is considered medically necessary in severe cases of toxic epidermal necrolysis and Stevens-Johnson syndrome
Toxic shock syndrome or toxic necrotizing fasciitis due to group A streptococcus IVIG is considered medically necessary in persons who are sufficiently ill to require critical care unit support and have documented presence of fasciitis and microbiological data consistent with invasive streptococcal infection (culture or Gram stain).

 

 

Indications 2 to 5 years 6+ years
Respiratory Infections    
URIs treated with antibiotics in last 12 months > 4 > 2
Otitis treated with antibiotics (per year) > 3 >1
Sinusitis episodes (per year) >2 >1
Chronic, treatment-resistant sinusitis (>1 mo) >1 >1
Pneumonias (per year) >2 >2
Invasive infections (sepsis, meningitis, osteomyelitis) >2 >2
Severe invasive infections >1 >1
Gastrointestinal Infections    
Chronic diarrhea due to rotavirus, other >1 >1
Chronic/recurrent Giardia lamblia infection >1 >1
Antibiotic Use    
Need for preventive antibiotic use >1 >1
Chronic antibiotic use without effect > 2 months > 2 months
Allergy to antibiotics > 1 > 1
Need for IV antibiotics to clear infection >1 >1

Adapted from: Sorensen and Moore, 2000; Jeffrey Modell Foundation, 2007; Sorensen and Paris, 2007.

The laboratory's own reference ranges should be used, where available.  If the laboratory's reference ranges are not submitted with the immunoglobulin level results, the following standard reference ranges may be applied.

 

Normal Immunoglobulin Levels (mg/dl) Normal IgG Subclass Levels (mg/dl)
AGE IgA IgG  IgM AGE IgG1 IgG2 IgG3 IgG4
1 - 2 mo 1 - 53 251 - 906 20 - 87 cord 435 - 1084 143 - 453 27 - 146 1 - 47
2 - 3 mo 3 - 47 206 - 601 17 - 105 0 - 3 mo 218 - 496 40 - 167 4 - 23 1 - 33
3 - 4 mo 4 - 73 176 - 581 24 - 101 3 - 6 mo 143 - 394 23 - 147 4 - 100 1 - 14
4 - 5 mo 8 - 84 172 - 814 33 - 108 6 - 9 mo 190 - 388 37 - 60 12 - 62 1 - 1
5 - 6 mo 8 - 68 215 - 704 35 - 102 9 mo - 3 yr 286 - 680 30 - 327 13 - 82 1 - 65
6 - 8 mo 11 - 90 217 - 904 34 - 125 3 - 5 yr 381 - 884 70 - 443 17 - 90 1 - 116
8 mo - 1 yr 16 - 84 294 - 1069 41 - 149 5 - 7 yr 292 - 816 83 - 513 8 - 111 1 - 121
1 - 2 yr 14 - 106 345 - 1213 43 - 173 7 - 9 yr 442 - 802 113 - 480 15 - 133 1 - 84
2 - 3 yr 14 - 123 424 - 1051 48 - 168 9 - 11 yr 456 - 938 163 - 513 26 - 113 1 - 121
3 - 4 yr 22 - 159 441 - 1135 47 - 200 11 - 13 yr 456 - 952 147 - 493 12 - 179 1 - 168
4 - 6 yr 25 - 154 463 - 1236 43 - 196 13 - 15 yr 347 - 993 140 - 440 23 - 117 1 - 183
6 - 9 yr 33 - 202 633 - 1280 48 - 207 15 yr & up 422 - 1292 117 - 747 41 - 129 1 - 291
9 - 11 yr 45 - 236 608 - 1572 52 - 242          
11 yr & up 70 - 312 639 - 1349 56 - 352          

Aetna considers IVIG therapy experimental and investigational for any of the following conditions (in alphabetical order):

Acquired factor VIII inhibitors
Acquired von Willebrand's disease
Acute lymphocytic leukemia
Acute lymphoblastic leukemia
Acute myeloid leukemia
Acute optic neuritis
Adrenoleukodystrophy
Alzheimer’s disease
Amyotrophic lateral sclerosis
Angioedema
Antiphospholipid syndrome
Aplastic anemia
Asthma
Attention deficit hyperactivity disorder
Autism
Autoimmune autonomic neuropathy
Autoimmune bullous skin diseases
Autoimmune chronic urticaria
Autoimmune inner ear disease
Autoimmune liver disease
Behçet's syndrome
Burkitt’s lymphoma
Cardiomyopathy, acute
Chronic fatigue syndrome
Chronic myelogenous leukemia
Chronic sinusitis
Clostridium difficile colitis
Complex regional pain syndrome
Congenital factor VII deficiency
Congenital heart block
Convulsive syndromes
Critical illness polyneuropathy
Cystic fibrosis
Degos disease
Depression
Dermatosis, autoimmune
blistering
Diabetes mellitus
Diabetic amyotrophy
Diffuse alveolar hemorrhage
Dravet's syndrome
Diamond-Blackfan anemia
Dysautonomia, acute idiopathic
Eczema
Encephalopathy

Endotoxemia
Epilepsy
Fahr's disease
Gastroenteropathy
Goodpasture’s syndrome
Hashimoto's encephalopathy
Hemolytic transfusion reaction
Hemolytic-uremic syndrome
Hemophagocytic syndrome (e.g., hemophagocytic lymphohistiocytosis)
Henoch-Schonlein purpura
HTLV-1 associated myelopathy
Hunter syndrome (mucopolysaccharidosis type II)
Idiopathic environmental illness and multiple chemical sensitivity syndrome
Idiopathic lumbosacral
plexopathy
Idiopathic pulmonary fibrosis
Immune-mediated neutropenia
Inclusion body myositis
Infertility
Intractable seizures
Isaacs syndrome
Landau-Kleffner syndrome
Leukemia, acute lymphoblastic
Limbic encephalitis
Lipidosis
Lower motor neuron syndrome
Malignancy, non-hematologic
Mannose-binding lectin deficiency
Maternal autoantibody-mediated cardiomyopathy
Mitochondrial encephalopathy
Multiple sclerosis - primary
progressive or secondary types
Myalgia, myositis, unspecified
Myalgic encephalomyelitis
Myelopathy, HTLV-I associated
Necrotizing enterocolitis
Neonatal lupus syndromes
Neonatal sepsis (treatment)
Neonatal sepsis (prophylaxis)
Nephritic syndrome
Nephropathy, membranous
Nephrotic syndrome
Neuromyelitis optica (Devic’s
disease)
Neuromyotonia (Isaacs’ syndrome)
Neurosarcoidosis
Nodular (follicular) lymphoma
Obsessive-compulsive disorder
Ophthalmopathy, euthyroid
Oral use of IVIG for any
indication
Orthostatic tachycardia syndrome
Otitis media, recurrent
Paraneoplastic cerebellar
degeneration
Paraneoplastic syndromes other than neuroblastoma

Paraproteinemic neuropathy (IgM variant
Parkinson’s disease
Parsonage-Turner syndrome (brachial neuritis)
Pediatric autoimmune
neuropsychiatric disorders
associated with streptococcal
infection (PANDAS)
Pediatric infection-triggered autoimmune neuropsychiatric disorders (PITAND)
POEMS syndrome **
Polyarteritis nodosa
Polyneuritis cranialis
Pre-thymectomy
Progressive lumbosacral
plexopathy
Pyoderma gangrenosum
Radiculoneuritis, Lyme
Recurrent otitis media
Recurrent fetal/pregnancy loss
Red cell aplasia not due to erythrovirus B19
Reducing the risk of post-partum exacerbation of multiple sclerosis
Rheumatic fever, carditis
Refractoriness to platelet
transfusion
Reiter's syndrome
Renal failure, acute
Rheumatoid arthritis (adult and
juvenile)
Scleroderma
Selective isolated IgA immunodeficiency
Sensory neuropathy
SICCA syndrome/Sjogren's syndrome
Small fiber neuropathy associated with sarcoidosis
Still's disease
Sydenham's chorea
Systemic vasculitides
Thrombocytopenia (non-immune, 
e.g., heparin-induced)
Thrombotic thrombocytopenic
purpura (TTP)
Tic disorders
Transverse myelopathy/myelitis
Uveitis
Vasculitis associated with other
connective tissue diseases
Viral myocarditis
Vogt-Koyanagi-Harada syndrome
Wegener’s granulomatosis

** The term "POEMS" is actually an acronym for the most common symptoms and signs of the syndrome: "P" - peripheral neuropathy (numbness, tingling, and weakness of the feet and hands); “O” - organomegaly (large organs, like the liver, lymph nodes and spleen); "E" - endocrinopathy (abnormal hormone levels including sex hormones, thyroid hormones, etc.); "M" - monoclonal plasma-proliferative disorder (a collection of abnormal bone marrow cells, called plasma cells); most patients will have at least on abnormal bone x-ray associated with these plasma cells; "S" - skin changes (increased skin pigment, increased body hair, thickening of the skin, etc).

Table: Brands of Immune Globulins and FDA-Approved Indications:

Brand of Immune Globulin FDA-Approved Indications 
Bivigam Primary humoral immunodeficiency
Carimune NF Primary immunodeficiencies, immune thrombocytopenic purpura
Flebogamma Primary immunodeficiencies
Gammagard Primary immunodeficiencies
Gammaked Primary immunodeficiencies, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy
Gammaplex Primary immunodeficiencies
Gammar-P I.V. Primary immunodeficiencies
Gamunex Primary immunodeficiencies, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy
Hizentra (subcutaneous) Primary immunodeficiencies
Iveegam EN Primary immunodeficiencies, Kawasaki syndrome
Octagam Primary immunodeficiencies
Panglobin Primary immunodeficiencies, immune thrombocytopenic purpura
Polygam S/D Primary immunodeficiencies, immune thrombocytopenic purpura, Kawasaki syndrome, B-cell chronic lymphocytic leukemia
Privigen Primary immunodeficiencies, immune thrombocytopenic purpura

Source: Drug Facts & Comparisons, 2009.

* Primary immunodeficiencies includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

** An intra-muscular formulation of immune globulin, GamaSTAN S/D, has been approved for the following indications: prophylaxis of hepatitis A; prevention or modification of measles (rubeola) in persons exposed fewer than 6 days previously; passive immunization against varicella in immunosuppressed patients; prophylaxis of rubella in pregnancy when therapeutic abortion is not an option; and prevention of serious infection in patients with IgG deficiencies.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
90281
90283
90284
Other CPT codes related to the CPB:
20200 - 20206
33930 - 33945
36430 - 36455
38221
38230
38232
38240
38241
50300 - 50380
62270
78630 - 78650
86325
86975 - 86978
95860 - 95887
95907 - 95913
95937
96360
+96361
96365
+96366
+96367
+96368
96369
+96370
+96371
HCPCS codes covered if selection criteria are met:
J1459 Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1556 Injection, immune globulin (bivigam), 500 mg
J1557 Injection, immune globulin, (gammaplex), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1559 Injection, immune globulin (hizentra), 100 mg
J1561 Injection, immune globulin, (Gamunex/Gamunex-C/Gammaked), nonlyophilized (e.g., liquid), 500 mg
J1566 Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg
J1568 Injection, immune globulin, (Octagam), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1569 Injection, immune globulin, (Gammagard liquid), nonlyophilized, (e.g., liquid), 500 mg
J1572 Injection, immune globulin, (Flebogamma / Flebogamma Dif), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1599 Injection, immune globulin, intravenous, non-lyophilized (eg, liquid), not otherwise specified, 500 mg
Other HCPCS codes related to the CPB:
J1830 Injection interferon beta-1b, 0.25 mg
J9212 - J9216 Injection, interferon alfacon-1, recombinant, 1 mcg, interferon alfa-2a, recombinant, 3 million units, interferon alfa-2b, recombinant, 1 million units, interferon alfa-N3, (human leukocyte derived), 250,000 IU, or interferon gamma-1b, 3 million units
Q3027 Injection, interferon beta-1a, 1 mcg for intramuscular use
S9338 Home infusion therapy, immunotherapy, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-9 codes covered if selection criteria are met:
040.82 Toxic shock syndrome
041.01 Infection streptococcus, group A
042 Human immunodeficiency virus [HIV] disease [bacteria control or prevention]
055.0 - 055.9 Measles [modification] [intramuscular use only]
079.83 Parvovirus B19
203.00 - 203.02 Multiple myeloma
203.10 - 203.12 Plasma cell leukemia
203.80 - 203.82 Other immunoproliferative neoplasms
204.10 - 204.12 Lymphoid leukemia, chronic [B-cell] [with hypogammaglobulinemia and recurrent infections or specific antibody deficiency]
279.00 Hypogammaglobulinemia, unspecified
279.04 Congenital hypogammaglobulinemia
279.05 Immunodeficiency with increased IgM
279.06 Common variable immunodeficiency [Good syndrome]
279.11 DiGeorge's syndrome
279.12 Wiskott-Aldrich syndrome
279.2 Combined immunity deficiency
279.50 Graft-versus-host disease, unspecified
279.51 Acute graft-versus-host disease
279.52 Chronic graft-versus-host disease
279.53 Acute on chronic graft-versus-host disease
283.0 Autoimmune hemolytic anemias [warm-type, refractory]
284.81 Red cell aplasia (acquired) (adult) (with thymoma)
286.0 Congenital factor VIII disorder
286.1 Congenital factor IX disorder
287.31 Immune thrombocytopenic purpura [when a rapid rise in platelet count is required, such as prior to surgery, to control excessive bleeding, or to avoid splenectomy]
287.4 Secondary thrombocytopenia [HIV associated, pediatric or adult, when criteria are met] [post-transfusion purpura]
287.5 Thrombocytopenia, unspecified
288.1 Functional disorders of polymorphonuclear neutrophils [Job's syndrome]
289.81 - 289.9 Other and unspecified diseases of blood and blood-forming organs
323.61 Infectious acute disseminated encephalomyelitis (ADEM) [refractory]
333.91 Stiff-man syndrome [unresponsive to other therapies]
340 Multiple sclerosis [relapsing-remitting when standard approaches have failed, become intolerable, or are contraindicated] [not covered for reducing the risk of post-partum exacerbation}
356.8 - 356.9 Other specified idiopathic and unspecified peripheral neuropathy
357.0 Acute infective polyneuritis [so severely affected that they at least require aid to walk, that the disorder is diagnosed during the first 2 weeks of the illness, and that there are no contraindications] [Miller-Fisher syndrome (MFS)]
357.81 Chronic inflammatory demyelinating polyneuritis
357.89 Other inflammatory and toxic neuropathy
358.00 - 358.01 Myasthenia gravis [treatment of acute crisis with decompensation] [other treatments unsuccessful or contraindicated]
446.1 Acute febrile mucocutaneous lymph node syndrome [MCLS] [Kawasaki disease]
694.4 - 694.8 Pemphigus, pemphigoid, or benign mucous membrane pemphigoid, and other specified bullous dermatoses [if failed has contraindications to conventional therapy or rapidly progressive disease in which clinical response could not be affected quickly enough using conventional agents] [not covered for autoimmune bullous skin diseases]
695.13 Stevens-Johnson syndrome
695.14 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome
695.15 Toxic epidermal necrolysis
710.0 Systemic lupus erythematosus [severe for whom other interventions have been unsuccessful, have become intolerable, or are contraindicated]
710.3 Dermatomyositis
710.4 Polymyositis [in persons who are resistant to first and second line therapies]
728.86 Necrotizing fasciitis [toxic, due to group A streptococcus]
773.0 - 773.2 Hemolytic disease of fetus or newborn, due to isoimmunization [not responding to phototherapy, to decrease need for exchange transfusion]
776.1 Transient neonatal thrombocytopenia
996.81 Complications of transplanted kidney
996.82 Complications of transplanted liver
996.83 Complications of transplanted heart
996.84 Complications of transplanted lung
996.85 Complication of transplanted bone marrow [prophylaxis in allogeneic or syngeneic transplant recipients within the first 100 days post-transplant; after 100 days post-transplant IVIG is indicated for recipients who are markedly hypogammaglobinemic (IgG level less than 400 mg/dL), or who have CMV, EBV or RSV infection]
996.86 Complications of transplanted pancreas
996.87 Complications of transplanted intestine
V01.4 Contact with or exposure to rubella [intramuscular use only]
V01.71 Contact with or exposure to varicella [passive immunization in immunosuppressed patients] [intramuscular use only]
V07.2 Prophylactic immunotherapy
V42.0 Organ or tissue replaced by transplant, kidney
V42.1 Organ or tissue replaced by transplant, heart
V42.6 Organ or tissue replaced by transplant, lung
V42.7 Organ or tissue replaced by transplant, liver
V42.81 Organ or tissue replaced by transplant, bone marrow [prophylaxis in allogeneic or syngeneic transplant recipients within the first 100 days post-transplant; after 100 days post-transplant IVIG is indicated for recipients who are markedly hypogammaglobinemic (IgG level less than 400 mg/dL), or who have CMV, EBV or RSV infection
V42.82 Organ or tissue replaced by transplant, peripheral stem cells replaced by transplant [prophylaxis in allogeneic or syngeneic transplant recipients within the first 100 days post-transplant; after 100 days post-transplant IVIG is indicated for recipients who are markedly hypogammaglobinemic (IgG level less than 400 mg/dL), or who have CMV, EBV or RSV infection]
V42.83 Pancreas replaced by transplant
V42.84 Intestines replaced by transplant
V49.83 Awaiting organ transplant status
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
008.45 Clostridium difficile intestinal infection
011.20 - 011.26 Tuberculosis of lung with cavitation
032.82 Diphtheritic myocarditis
036.43 Meningococcal myocarditis
074.23 Coxsackie myocarditis
088.81 Lyme disease
093.82 Syphilitic myocarditis
099.3 Reiter's disease
130.3 Myocarditis due to toxoplasmosis
135 Sarcoidosis
136.9 Unspecified infectious and parasitic diseases
140.0 - 199.2 Malignant neoplasm (except hematologic)
200.20 - 200.28 Burkitt’s tumor or lymphoma
202.00 - 202.08 Nodular (follicular) lymphoma
204.00 - 204.02 Lymphoid leukemia, acute
205.00 - 205.02 Acute myeloid leukemia
205.10 - 205.12 Chronic myelogenous leukemia
209.00 - 209.30 Malignant carcinoid tumor
249.00 - 249.91 Secondary diabetes mellitus
250.00 - 250.93 Diabetes mellitus
272.7 Lipidoses
273.1, 273.2, 273.9 Monoclonal paraproteinemia, other paraproteinemias, or unspecified disorder of plasma protein metabolism
277.00 - 277.09 Cystic fibrosis
277.2 Other disorders of purine and pyrimidine metabolism
277.5 Mucopolysaccharidosis (Hunter’s syndrome)
277.6 Other deficiencies of circulating enzymes
283.11 Hemolytic-uremic syndrome
284.01 - 284.9 Aplastic anemia
286.3 Congenital deficiency of other clotting factors [congenital factor VII deficiency]
286.4 von Willebrand's disease
287.0 Allergic purpura (Henoch-Schonlein)
288.00 - 288.09 Neutropenia
288.4 Hemophagocytic syndromes [hemophagocytic lymphohistiocytosis]
296.20 - 296.36 Major depression
299.00 - 299.01 Autistic disorder
300.3 Obsessive-compulsive disorder
311 Depression
314.01 Attention deficit disorder with hyperactivity
307.20 - 307.23 Tics
323.0 - 323.9 Encephalitis/myelitis and encephalomyelitis [limbic]
330.0 Leukodystrophy
331.0 Alzheimer's disease
332.0 - 332.1 Parkinson's disease
333.4 Huntington's chorea
335.20 Amyotrophic lateral sclerosis
337.20 - 337.29 Reflex sympathetic dystrophy [complex regional pain syndrome]
337.9 Unspecified disorder of autonomic nervous system [autoimmune autonomic neuropathy]
341.0 Neuromyelitis optica [Devic's syndrome]
345.00 - 345.91 Epilepsy and recurrent seizures
348.30 - 348.39 Encephalopathy, not elsewhere classified [mitochondrial encephalopathy]
352.6 Multiple cranial nerve palsies
353.5 Neuralgic amyotrophy [diabetic] [Parsonage-Turner syndrome]
357.4 Polyneuropathy in other diseases classified elsewhere [small fiber neuropathy]
358.8 Other specified myoneural disorders [Isaacs syndrome]
364.00 - 364.3 Acute and subacute iridocyclitis, chronic iridocyclitis, certain types of iridocyclitis, and unspecified iridocyclitis
377.30 - 377.32 Optic neuritis
390 Rheumatic fever without mention of heart involvement
391.0 - 391.9 Rheumatic fever with heart involvement
392.9 Rheumatic chorea without mention of heart involvement [Sydenham's chorea]
422.0 Acute myocarditis in diseases classified elsewhere
425.4 Other primary cardiomyopathies
446.0 Polyarteritis nodosa
446.21 Goodpasture's syndrome
446.4 Wegener's granulomatosis
446.6 Thrombotic microangiopathy
447.8 Other specified disorders of arteries and arterioles [Degos disease]
473.0 - 473.9 Chronic sinusitis
493.00 - 493.92 Asthma
516.3 Idiopathic fibrosing alveolitis [idiopathic pulmonary fibrosis]
531.00 - 538 Diseases of stomach and duodenum
555.0 - 558.9 Non-infectious enteritis and colitis
560.0 - 564.9 Other diseases of intestines
557.0 Acute vascular insufficiency of intestine
580.0 - 581.9 Nephritis and nephrotic syndrome
582.2 Chronic glomerulonephritis, with lesion of membranoproliferative glomerulonephritis
583.1 Nephritis and nephropathy, not specified as acute or chronic, with lesion of membranous glomerulonephritis
584.5 - 584.9 Acute renal failure
628.0 - 628.9 Infertility, female
686.01 Pyoderma gangrenosum
692.9 Eczema
694.4 - 694.8 Bullous dermatoses
708.8 Other specified urticaria
710.1 Systemic sclerosis
710.2 Sicca syndrome [Sjogren's syndrome]
714.0 - 714.9 Rheumatoid arthritis
729.1 Myalgia and myositis, unspecified
746.86 Congenital heart block
771.81 Septicemia [sepsis] of newborn
780.39 Other convulsions
780.71 Chronic fatigue syndrome
785.0 Tachycardia, unspecified [orthostatic tachycardia syndrome]
785.59 Other shock without mention of trauma
786.30 Hemoptysis, unspecified [diffuse alveolar hemorrhage]
795.79 Other and unspecified nonspecific immunological findings
995.1 Angioneurotic edema
V13.29 Other genital system and obstetric disorders
Other ICD-9 codes related to the CPB:
075 Infectious mononucleosis [Epstein Barr virus]
078.5 Cytomegaloviral disease
079.6 Respiratory syncytial virus (RSV)
466.11 Acute bronchiolitis due to RSV
480.1 Pneumonia due to RSV
771.1 Congenital Cytomegalovirus Infection
200.00 - 202.98 Lymphosarcoma and reticulosarcoma
204.20 - 208.91 Subacute, other, and unspecified lymphoid leukemia, myeloid leukemia, monocytic leukemia, other specified leukemia, and leukemia of unspecified cell type
323.81 Other causes of encephalitis and encephalomyelitis [noninfectious acute disseminated encephalomyelitis (ADEM)] [Rasmussen's encepahlitis or syndrome]
333.2 Myoclonus
336.3 Myelopathy in other diseases classified elsewhere
336.8 Other myelopathy
357.82 Critical illness polyneuropathy [acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN)]
358.1 Myasthenic syndromes in diseases classified elsewhere [Eaton-Lambert syndrome]
379.59 Other irregularities of eye movement
446.20 - 446.29 Hypersensitivity angiitis
728.85 Spasm of muscle
728.87 Muscle weakness (generalized)
780.66 Febrile nonhemolytic transfusion reaction
781.3 Lack of coordination
999.89 Other transfusion reaction
V42.82 Peripheral stem cells replaced by transplant


The above policy is based on the following references:
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  31. Achiron A, Gabbay U, Gilad R, et al. Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology. 1998;50(2):398-402.
  32. Sorensen PS. Intravenous immunoglobulin G therapy: Effects of acute and chronic treatment in multiple sclerosis. Mult Scler. 1996;1(6):349-352.
  33. Poehlau D, Federlein J, Postert T, et al. Intravenous immunoglobulin (IVIG) treatment for patients with primary or secondary progressive multiple sclerosis -- outline of a double- blind randomized, placebo-controlled trial. Mult Scler. 1997;3(2):149-152.
  34. Sorensen PS, Wanscher B, Schreiber K, et al. A double-blind, cross-over trial of intravenous immunoglobulin G in multiple sclerosis: Preliminary results. Mult Scler. 1997;3(2):145-148.
  35. Fazekas F, Deisenhammer F, Strasser-Fuchs S, et al. Treatment effects of monthly intravenous immunoglobulin on patients with relapsing-remitting multiple sclerosis: Further analyses of the Austrian Immunoglobulin in MS study. Mult Scler. 1997;3(2):137-141.
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    ShortForms/iv_immunoglobulin_products.htm. Accessed June 24, 2002.
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  52. Kimata H. High-dose intravenous gammaglobulin treatment of hyperimmunoglobulinemia E syndrome. J Allergy Clin Immunol. 1995;95:771-774.
  53. Bain PG, Motomura M, Newsom-Davis J, et al. Effects of intravenous immune globulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology. 1996;47:678-683.
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  55. Clegg A, Bryant J, Milne R. Disease modifying agents in multiple sclerosis. Health Technol Assess. 2000;4(9):1-101.
  56. Center for Medicare and Medicaid Services (CMS). Intravenous immune globulin for autoimmune mucocutaneous blistering diseases. Decision Memorandum. CPG-00109N. Baltimore, MD: CMS; January 22, 2002. Available at: http://cms.hhs.gov/coverage.8b3-kkk2.asp. Accessed July 1, 2002.
  57. Fanaroff AA, Korones SB, Wright LL, et al. A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birth-weight infants. N Engl J Med. 1994;330(16):1107-1113.
  58. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet. 1997;349:225-230.
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  60. Wu HM, Tang JL, Sha ZH, et al. Interventions for preventing infection in nephrotic syndrome.  Cochrane Database Syst Rev. 2004;(2):CD003964. 
  61. Hughes RAC, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010;(6):CD002063. 
  62. Alejandria MM, Lansang MA, Dans LF, Mantaring JBV. Intravenous immunoglobulin for treating sepsis and septic shock. Cochrane Database Syst Rev. 2002;(1):CD001090. 
  63. Gray O, McDonnell GV, Forbes RB. Intravenous immunoglobulins for multiple sclerosis. Cochrane Database Syst Rev. 2003;(3):CD002936. 
  64. Brocklehurst P. Interventions for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev. 2002;(1):CD000102.
  65. Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2008;(1):CD002277. 
  66. Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. 2002;(3):CD003313. 
  67. Bain PG, Motomura M, Newsom-Davis J, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology. 1996;47:678-683.
  68. Maddison P, Newsom-Davis J. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2005;(2):CD003279. 
  69. Daya S, Gunby J, Clark D A. Intravenous immunoglobulin therapy for recurrent spontaneous abortion: A meta-analysis. Am J Reprod Immunol. 1998;39(2):69-76.
  70. Jenson HB, Pollock BD. Meta-analyses of the effectiveness of intravenous immune globulin for prevention and treatment of neonatal sepsis. Pediatrics. 1997:99(2):E2.
  71. Ballow M. Primary immunodeficiency disorders: Antibody deficiency. J Allergy Clin Immunol. 2002;109(4):581-591.
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  80. Cilliers AM, Manyemba J, Saloojee H. Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database Syst Rev. 2003;(2):CD003176. 
  81. Jordan S, Cunningham-Rundles C, McEwan R. Utility of intravenous immune globulin in kidney transplantation: Efficacy, safety, and cost implications. Am J Transplant. 2003;3(6):653-664.
  82. Glotz D, Antoine C, Julia P, et al. Desensitization and subsequent kidney transplantation of patients using intravenous immunoglobulins (IVIg). Am J Transplant. 2002;2(8):758-760.
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  84. Sonnenday CJ, Ratner LE, Zachary AA, et al. Preemptive therapy with plasmapheresis/intravenous immunoglobulin allows successful live donor renal transplantation in patients with a positive cross-match. Transplant Proc. 2002;34(5):1614-1616.
  85. Al-Uzri AY, Seltz B, Yorgin PD, et al. Successful renal transplant outcome after intravenous gamma-globulin treatment of a highly sensitized pediatric recipient. Pediatr Transplant. 2002;6(2):161-165.
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  90. Glotz D, Haymann JP, Niaudet P, et al. Successful kidney transplantation of immunized patients after desensitization with normal human polyclonal immunoglobulins. Transplant Proc. 1995;27(1):1038-1039.
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  93. Levy Y, George J, Fabbrizzi F, et al. Marked improvement of Churg-Strauss vasculitis with intravenous gammaglobulins. South Med J. 1999;92(4):412-414.
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  97. Hamilos DL, Christensen J. Treatment of Churg-Strauss syndrome with high-dose intravenous immunoglobulin. J Allergy Clin Immunol. 1991;88(5):823-824.
  98. Levy Y, Sherer Y, George J, et al. Serologic and clinical response to treatment of systemic vasculitis and associated autoimmune disease with intravenous immunoglobulin. Int Arch Allergy Immunol. 1999;119(3):231-238.
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  100. British Columbia Ministry of Health Services, Provincial Blood Coordinating Office. IVIG utilization management handbook. 1st ed. Vancouver, BC: British Columbia Ministry of Health Services; April 2002. Available at: http://www.bloodlink.bc.ca/documents/ivighandbook2.pdf. Accessed June 30, 2003.
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  103. Hughes RAC, Wijdicks EFM, Barohn R, et al. Practice parameter: Immunotherapy for Guillian-Barre syndrome. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003;61:736-740. Available at: http://www.neurology.org/cgi/content/abstract/61/6/736. Accessed March 10, 2004.
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  109. Salcedo J, Keates S, Pothoulakis C, et al. Intravenous immunoglobulin therapy for severe Clostridium difficile colitis. Gut. 1997;41(3):366-370.
  110. Leung DY, Kelly CP, Boguniewicz M, et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr. 1991;118(4 ( Pt 1)):633-637.
  111. Ohlsson A, Lacy J. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database Syst Rev. 2004;(1):CD000361.
  112. Fanaroff AA, Korones SB, Wright LL, et al. A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1994;330(16):1107-1013.
  113. Kinney J, Mundorf L, Gleason C, et al. Efficacy and pharmacokinetics of intravenous immune globulin administration to high-risk neonates. Am J Dis Child. 1991;145(11):1233-1238.
  114. Malik S, Giacoia GP, West K. The use of intravenous immunoglobulin (IVIG) to prevent infections in bronchopulmonary dysplasia: Report of a pilot study. J Perinatol. 1991;11(3):239-244.
  115. Buemi M, Pettinato G, Palella S, et al. Treatment of the nephritic syndrome in elderly with human intravenous immunoglobulins. Contrib Nephrol. 1993;105:172-179.
  116. Hebert AA, Bogle MA. Intravenous immunoglobulin prophylaxis for recurrent Stevens-Johnson syndrome. J Am Acad Dermatol. 2004;50(2):286-288.
  117. Campione E, Marulli GC, Carrozzo AM, et al. High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venereol. 2003;83(6):430-432.
  118. Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: Seven cases and review of the literature. Pediatrics. 2003;112(6 Pt 1):1430-1436.
  119. Sidwell RU, Swift S, Yan CL, et al. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin. Int J Clin Pract. 2003;57(7):643-645.
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