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.

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

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.

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

** 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:

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.