Evidence for the use of intravenous immunoglobulins--a review of the literature.

Introduction

Intravenous immunoglobulins (IVIg) are gamma globulins purified from the pooled plasma of thousands of donors, typically containing more than 95% of unmodified immunoglobulin G (IgG) and only trace amounts of IgA or IgM. Immune globulin products from human plasma were first used in 1952 to treat immune deficiencies. About 30 years later, Paul Imbach observed that patients with immune thrombocytopenia and agammaglobulinemia receiving immunoglobulins as immune replacement therapy recovered from their thrombocytopenia [ 1 ]. This was the first observation to suggest treatment of autoimmune diseases with IVIg. Later on, the ability to administer large quantities of immunoglobulin intravenously was gained owing to technological advances, among them the improvement in plasma fractionation. As a result, IVIg slowly became an important treatment option in a number of diseases beyond primary immune deficiencies, including autoimmune and acute inflammatory conditions, most of them off-label indications. These indications have crossed over into almost every medical specialty. The US Food and Drug Administration (FDA) has approved the use of IVIg for the following six conditions: primary immunodeficiencies, immune thrombocytopenic purpura (ITP), Kawasaki disease, hematopoietic stem cell transplantation, chronic B cell lymphocytic leukemia, and pediatric HIV. Many off-label indications have emerged; some of these new indications for IVIg are based on solid clinical evidence; others are based on relatively few data or anecdotal reports (case series, case reports). This lack of firm evidence is due to the difficulty in performing appropriate clinical trials in diseases with low prevalence. There is a need for an evidence-based guidance for the use of IVIg to help improve patient care consistency.

Another issue is the efficacy of different preparations of IVIg. The FDA has recommended the use of particular preparations of IVIg for each labeled indication in accordance to the specific preparation used to demonstrate a beneficial effect. Of course, there is selection bias since generally only a few preparations have been tested for a given disease. This is in recognition of the difficulty to reproduce the properties of an IVIg preparation, which may vary from one manufacturer to the other due to differences in the donor population, number of donors, period of donation, production methods, virus/bacteria inactivation methods, etc. IVIg properties may also vary from batch to batch made by the same manufacturer, complicating homogeneity even more.

Possible mechanisms of action of IVIg in autoimmune and inflammatory diseases are: intact Fc-dependent blockage of IgG (as in ITP), inhibition of membrane attack complexes (C5b-C9) and activated components C3b and C4b (as in Kawasaki's disease), and anti-idiotypes against autoantibodies (as in acquired hemophilia due to autoantibodies against factor VIII). IVIg also contains various cytokines and natural antibodies that may act against pathogens, altered molecules, cells, autoreactive B cell clones, and tumors.

Methods

A panel of immunologists and internists with experience in IVIg therapy reviewed the medical literature indexed in PubMed using specific terms for each specific disease/condition AND (“IVIg” OR “IgIV” OR “Intravenous Immunoglobuli*” OR “gamma globuli*”). There was no limitation on language, year of publication, or publication status. We used all clinical data ranging from multicentered randomized controlled trials (RCT) and meta-analysis to case reports. From each article, we extracted details of the study design, number of patients, type of intervention including the dose and IVIg preparation used (if mentioned), and response to treatment. The relevant data were summarized in a hierarchical manner according to the study design and number of participants. When evidence was based on higher level of evidence studies, such as RCTs, lower levels of evidence studies (such as case control studies) were disregarded. Specific diseases were classified in tables according to the specialty they belong to and are followed by a short summary of recommendations, including the level of evidence and the strength of recommendation, as assessed by known guidelines (Table 1 ) [ 2 ]. To our knowledge, this is the first comprehensive review which summarizes all up-to-date published data regarding the usage of IVIg in autoimmune diseases, immune deficiencies, and other indications. Table 1 Recommendation guidelines [ 2 ] Level of evidence A: more than one randomized controlled trial (RCT)/meta-analysis B: a single RCT or well-designed nonrandomized trial like prospective observational registries (case–controls, cohorts). C: expert consensus: this includes case reports and retrospective series; here, the expert decides based on his experience Strength of recommendation Class I: conditions for which there is evidence and/or general agreement that a given procedure/therapy is useful and effective Class II: conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of performing the procedure/therapy Class IIa: weight of evidence/opinion is in favor of usefulness/efficacy Class IIb: usefulness/efficacy is less well established by evidence/opinion Class III: conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful/effective and in some cases may be harmful

Results

The tables below summarize the clinical data gathered from studies dealing with IVIg treatment for different conditions. Each table is followed by our evidence-based recommendations for the usage of IVIg ( Table 2 ). Table 2 The use of intravenous immunoglobulins in rheumatologic diseases Disease Ref. Study design Intervention including dose and IVIg preparation used Number of patients Results/response Systemic lupus erythematosus (SLE) systemic flare-up [ 36 ] Controlled trial IVIg 0.4 g/kg for 5 days, between 1 and 8 monthly courses (mean 5; ISIVEN-Instituto Sierovaccinogeno, Italiano ISI SpA.) 20 patients with active SLE Beneficial clinical response in 17 out of 20 pts ( p < 0.0001); especially in arthritis, fever, thrombocytopenia, and CNS lupus [ 37 ] Uncontrolled multicenter trial IVIg 0.4 g/kg for 5 days 13 females with acute exacerbation of SLE After IVIg treatment, the modified European Consensus Lupus Activity Measurement (mECLAM) declined in 12 out of 13 pts by ≥3 points ( p = 0.0002) [ 38 ] Uncontrolled trial 30 g of sulfonated IVIg preparation on days 1–4 and 21–24 12 patients with mild-to-moderate active SLE Within 6 weeks, the mean Systemic Lupus Activity Measure (SLAM) score declined from 7.3 to 5.25 ( p < 0.01); in a minority, this effect lasted 5–12 months [ 19 ] Retrospective trial Review of medical records of patients with SLE that were treated with low-dose IVIg (0.5 g/kg) for several courses 62 patients Clinical improvement in most disease manifestations including pericarditis; not including thrombocytopenia and alopecia Lupus myocarditis [ 39 ] Case series IVIg 0.4 g/kg per day for 5 days, in addition to CP or MMF (given to 2 patients) 3 patients with lupus myocarditis and severe deterioration in contractile functions; high-dose CS had little effect Marked clinical improvement; decreased need for CS [ 40 ] Case report IVIg 0.4 g/kg per day for 5 days 1 patient with lupus myocarditis refractory to CS Marked improvement of severe cardiac dysfunction after one course of IVIg SLE and thrombocytopenia [ 41 ] Retrospective trial IVIg 2 g/kg for 2 to 5 days 31 patients with severe thrombocytopenia associated with SLE refractory to PD treatment A transient response was observed in 20 patients (65%); no sustained response was observed Subacute cutaneous lupus erythematosus (SCLE) [ 42 ] Case series IVIg with starting doses of 1 g/kg for 2 days, followed by 0.4 g/kg monthly, until disease resolution or for 6 months 12 patients with resistant SCLE 5 patients had complete or near-complete clearing of their skin disease; two had partial improvement and 3 had limited responses [ 43 ] Case series IVIg 0.3 g/kg per day for 5 days each month for 12 months 7 patients with skin disease (5 had systemic LE; two had SCLE) IVIg was unable to control cutaneous disease efficiently [ 44 ] Case series IVIg 3 patients with SCLE resistant to topical and systemic therapy Good response [ 45 ] Case report IVIg 2 g/kg monthly 30-year-old woman with SCLE Good response Various manifestations of SLE [ 46 ] Various case reports Different IVIg preparations and doses 26 patients with specific lupus manifestations refractory to standard Tx.: autoimmune hemolytic anemia (2), acquired factor VIII inhibitors (2), acquired von Willebrand disease (2), pure red cell aplasia(3), pancytopenia (1), myelofibrosis (1), pneumonitis (2), pleural effusion (1), pericarditis (2), myocarditis (2), CNS lupus (6), peripheral neuropathy (1), polyradiculoneuropathy (1) Improvement of SLE-related condition For lupus nephritis, see kidney section For Kawasaki disease, see cardiology section Kikuchi Disease [ 47 ] Case report IVIg 0.4 g/kg per day for 3 days A 35-year-old patient with Kikuchi, refractory to steroids and thalidomide A definite improvement in her facial swelling occurred within 4 days, followed by gradual but complete resolution of lymphadenopathy over the subsequent 8 weeks, despite stopping steroid medication [ 48 ] Case report IVIg 1 g/kg per day for 2 days, plus PD (2 mg/kg per day) 2 children who had Kikuchi complicated with hemophagocytic syndrome One responded dramatically; second case responded partially to IVIg and fully after PD was added Still’s disease [ 49 ] Uncontrolled trial Patients received monthly IVIg 7 patients unresponsive or poorly responsive to nonsteroidal anti-inflammatory drugs 5 patients responded after 4–6 treatments; 2 failed to respond [ 50 ] Uncontrolled trial Between 1 and 8 IVIg monthly infusions with a dose of 1 g/kg per day for 2 days 7 patients suffering from adult Still's disease All patients improved but relapsed after 3–24 months [ 51 ] Case report 2 courses of IVIg 1 g/kg for 2 days 23-year-old patient with flare-up of disease while taking salicylates at gestational week 22 Significant clinical and laboratory improvement Granulomatous arteritis (GA, Wegener's granulomatosis) [ 52 ] Multicentered RCT 14 patients received IVIg 2 g/kg in 5 days (sandoglobulin Novartis) vs. 14 placebo 34 patients with ANCA-associated vasculitis (GA or MPA), refractory to CS or CP Reduction in Birmingham Vasculitis Activity Score of 50% in 14/17 and 6/17 of the IVIg and placebo groups, respectively [ 53 ] Uncontrolled trial Patients received IVIg (Sandoglobulin) 14 patients with GA who responded poorly to standard therapy All patients were in full and partial remission after 8 weeks; clinical benefit was maintained a year later [ 54 ] Uncontrolled trial Single or multiple courses of IVIg, 30 g/day, over 5 days 15 patients with GA who responded poorly to standard therapy 40% of patients benefited from IVIg treatment but without complete remission [ 55 ] Uncontrolled trial Monthly IVIg, 0.4 g/kg for 5 days, 1–6 cycles (Isiven Instituto Sierovaccinogeno, Italiano ISI SpA.) 10 patients with GA, CSS, or undifferentiated vasculitis which were refractory to standard treatment IVIg treatment was found beneficial in 6 out of the 10 patients [ 56 ] Uncontrolled trial IVIg 0.5 g/kg per day for 4 days; Sandoglobulin (Sandoz, Basel, Switzerland) 3 patients with GA not treated with immunosuppressants before One patient had full remission; one had transitional response; one had no response Microscopic polyangitis (MPA) [ 57 ] Uncontrolled trial IVIg 0.4 g/kg per day for 5 days, before or along with CS or CP (kenketsu velilon-I, Teijin Co., Ltd., Tokyo or kenketsu Glovenon-I, Nihon pharmaceutical Co., Ltd., Tokyo, Japan) 30 patients with MPA plus rapidly progressive glomerulonephritis At 6 months, renal and general survival were 92% and 93%, respectively, compared to 70% and 74% with conventional therapy in other studies [ 56 ] Uncontrolled trial IVIg 0.5 g/kg per day for 4 days (Sandoglobulin, Sandoz, Basel, Switzerland) 3 patients with MPA not treated with immunosuppressants before One patient had full remission; one had transitional response; one had no response [ 53 ] Uncontrolled trial Patients received IVIg (Sandoglobulin) 11 patients with MPA who responded poorly to standard therapy 8 weeks after IVIg, all patients were in full and partial remission, clinical benefit was maintained 12 months later in most patients Churg–Strauss syndrome (CSS) [ 58 ] Controlled trial All patients received PS and CP in severe cases; 9 received monthly PP, followed by IVIg 1 g/kg for 2 days (Ig vena N IVH; Sclavo, Siena, Italy) 18 patients with CSS After 12 months, all patients in the IVIg group and 4 (44%) in the control group were in remission; a significant favorable outcome was kept after 3 years ( p < 0.01) [ 59 ] Case series Daily IVIg 0.4 g/kg for 5 days 5 patients with cardiac CSS who showed poor response to PS ± CP Neuropathy improved; EF of patients improved from 35.2% to 61% ( p < 0.02) [ 55 ] Case report 5–6 courses of monthly IVIg, each course 0.4 g/kg for 5 days (Isiven Instituto Sierovaccinogeno, Italiano ISI SpA.) 2 patients with CSS, nonresponsive to standard treatment First patient had no improvement; second patient had clinical and laboratory improvement and was steroid-spared Autoimmune hepatitis (AIH) [ 60 ] Case report IVIg was initiated because of adverse affects of long-term steroid therapy A patient with chronic AIH Immediate clinical, serological, and histological improvement Autoimmune features in hepatitis C virus (HCV) infection [ 61 ] RCT IVIg 0.4 g/kg for 5 days, and then IFN alpha 3 times a week, compared to treatment with IFN alpha alone 42 patients with HCV and autoimmune phenomena A higher percentage of patients who received IFN alpha plus IVIg showed complete virological and histological responses Henoch–Schönlein purpura (HSP) [ 62 ] Cohort study IVIg 1 g/kg for 2 days, every month for 3 months (Biotransfusion, Roissy, France) 11 adult patients with severe IgA nephropathy (9 idiopathic, 2 with HSP) Substantial improvement in glomerular filtration rate and kidney functions; 2 patients with HSP had resolution of other systemic symptoms [ 63 ] Case report IVIg (Tegelines) 1 g/kg per day for 2 days A 10-year-old boy with HSP and severe abdominal manifestations refractory to treatment with CS Digestive symptoms disappeared within 3 days [ 64 ] Case report Patient was treated with IVIg A 26-year-old woman with HSP with nephrotic syndrome refractory to CS Dramatic resolution [ 65 ] Case report IVIg (polyglobulin N containing maltose) 0.4 g/kg, for 2 days 46-year-old man with HSP and MPGN Developed hemolysis and rapid deterioration renal function [ 66 ] Case report IVIg 1 g/kg for 2 days 56-year-old man with HSP and severe digestive manifestations The patient's purpura and abdominal syndrome improved dramatically Mixed connective tissue disease (MCTD) [ 67 ] Case report IVIg 0.4 g/kg for 5 days A woman with MCTD and fasciitis Quick improvement of her symptoms and decreased CRP [ 68 ] Case report Patient was treated with IVIg A 69-year-old man with MCTD and nonresponsive skin eruptions Successful control of disease Systemic sclerosis (SSc) [ 69 ] Controlled trial IVIg 0.4 g/kg daily for 5 days, monthly for 3–6 cycles 15 patients with SSc Treatment resulted in significant improvement in quality of life ( p = 0.03) and a decrease in Rodnan skin score ( p < 0.001) [ 70 ] Case series IVIg 0.4 g/kg daily for 5 days 5 patients with diffuse SSc Marked long-term improvement in skin thickness from 2 weeks of treatment ( p < 0.01) [ 71 ] Controlled trial Monthly IVIg 0.4 g/kg for 4 days, for 6 months 7 female patients with SSc (5 limited, 2 diffuse), with a severe refractory joint involvement Significant improvement in joint swelling and pain ( p < 0.03), as well as skin score ( p < 0.003), after 6 months of therapy [ 72 ] Case report 3–6 cycles of IVIg 0.4 g/kg for 5 days; ISIVEN (Instituto Sierovaccinogeno, Italiano ISI SpA, Italy) 3 patients with rapid deteriorating SSc refractory to treatment All patients had a significant decrease in their skin score For scleromyxedema, see dermatology section For Evan's syndrome, see hematology section Juvenile rheumatoid arthritis (JRA) [ 73 ] Multicentered RCT Bimonthly IVIg 1.5–2.0 g/kg for the first 2 months, then monthly for up to 6 months (Iveegam, Immuno AG, Vienna) after 3 and a half months was switched to placebo 25 patients with resistant JRA 19 (76%) had moderate to large improvement; the group which switched to placebo showed rapid loss of this effect [ 74 ] RCT Patients were additionally treated with high-dose IVIg or MP 20 patients with JRA treated with MTX and CS Clinical effects were rapid in both groups [ 75 ] Retrospective cohort IVIg monthly for 3–54 months 27 patients with systemic JRA 20 patients responded after 6 months, especially systemic features and CS dependence [ 76 ] Controlled trial High-dose IVIg 16 children with severe juvenile chronic arthritis Mild–moderate systemic, articular and laboratory improvement in most patients Rheumatoid arthritis (RA) [ 77 ] RCT IVIg 5 g/kg every 3 weeks for 6 courses vs albumin 20 patients with refractory RA No significant differences between treatment groups were noted during the 18-week trial [ 78 ] Controlled trial Patients were treated with IVIg 11 patients with refractory RA In 6 patients, clinical results were impressive; lasting responses could be achieved in 3 patients only [ 79 ] Case report IVIg 1 g per day for 2 days, monthly for 3 months 4 patients with severe refractory RA who have failed at least 4 second-line drugs None of the patients improved or worsened [ 80 ] Case report IVIg 0.4 g/kg for 5 days A 50-year-old woman with acute systemic RA refractory to treatment with CS, CP, or PP Clinical improvement 3 days after IVIg treatment Sjögren's disease [ 81 ] Case series 3 monthly courses of IVIg 0.4 g/kg body for 5 days 5 Sjögren patients complicated with ataxic sensory neuropathy, refractory to CS or PP 4 patients showed remarkable improvement, 2 of whom responded after the first course [ 82 ] Case report IVIg 0.4 g/kg for 5 days A patient with long-standing Sjögren's that developed a painful sensory neuropathy Remarkable clinical improvement and reduction of pain [ 83 ] Case report IVIg 0.4 g/kg for 5 days every 3 weeks A patient with Sjögren syndrome complicated with ataxic sensory neuropathy Remarkable improvement that subsided after switching to CS but regained after reintroduction to IVIg despite withdrawal of CS For antiphospholipid syndrome, see gyneco-obstetric section Polymyositis (PM) and dermatomyositis (DM) [ 84 ] RCT Received PD 25 mg plus IVIg 2 g/kg or placebo every month for 3 months 15 patients with treatment-resistant DM Significant improvement of muscle strength ( p < 0.018) and neuromuscular symptoms ( p < 0.035), with IVIg treatment compared to placebo [ 85 ] Controlled trial IVIg or standard therapy 16 patients with PM or DM Clinical and functional remission in a higher percentage (81%) that was maintained after a mean 5-year follow-up period, as compared to control group ( p < 0.001) [ 86 ] Controlled trial IVIg 0.4 g/kg per day for 5 days in addition to CS (Benesis Corporation, Osaka, Japan). 15 patients with Dm (7) or PM (8), who were refractory to traditional CS therapy Significant improvement in muscle strength, daily activity scores with no severe adverse reactions Inclusion Body myositis (IBM) [ 87 ] RCT Randomized to receive IVIg or placebo monthly for 3 months 36 patients with IBM, treated with high dose PD No clinical significant difference [ 88 ] RCT IVIg 2 g/kg Vs placebo 22 patients with sporadic inclusion body myositis No significant changes between groups according to modified Medical Research Council (MRC) score; mild improvement with IVIg according to Neuromuscular Symptom Score (NSS) [ 89 ] RCT IVIg 2 g/kg vs placebo monthly for 3 months 19 patients with IBM No significant changes between the groups according to MRC score; significant improvement in swallowing with IVIg ( p < 0.05) Behcet's disease (BD) [ 90 ] Case series 0.4 g/kg daily of IVIg (Omr- IgG -am, a 5% solution of human normal immunoglobulin G; Omrix Biopharmaceuticals Ltd, Nes-Ziona, Israel) 5 times in the first week, an additional 3 applications in the first month, once every 20 days for the next 3 months, then every 6 weeks for 1 year 6 eyes of 4 patients with ocular BD refractory to CS and cyclosporin A All 6 eyes of all 4 patients showed good response to IVIg therapy [ 91 ] Case report IVIg was started with 5 daily doses of 0.4 g/kg followed by reinforcement doses of 0.4 g/kg at 2-week intervals A 28-year-old man with BD suffering from severe leg, mouth, and scrotal ulcers and phlebitis resistant to immunosuppressants After 4 days, the ulcers started to heal; 2 months later, the patient became totally pain free and walked without limping

SLE—systemic flare-up

Level of evidence B

Systemic lupus erythematosus (SLE) is a multisystemic disease with various manifestations. There is some evidence that IVIg, given in patients without an increased risk for thromboembolic events or renal failure, is a safe and beneficial adjunct therapy for SLE patients with systemic flare-ups who are resistant to or refuse conventional treatment ( strength of recommendation I ).

Lupus myocarditis

Level of evidence C

Lupus myocarditis is an uncommon but severe complication of SLE. There is no consensus on the specific treatment of SLE myocarditis. Most reports describe treatment with high-dose corticosteroids (CS), followed by either cyclophosphamide or azathioprine, in addition to conventional treatment for heart failure. There is little evidence that IVIg is effective when immunosuppressive therapy fails ( strength of recommendation II ).

SLE and thrombocytopenia

Level of evidence B

As with the treatment of ITP, IVIg seems to be useful in managing the bleeding complications of patients with lupus-associated thrombocytopenia ( strength of recommendation I ).

Subacute cutaneous lupus erythematosus

Level of evidence C

Standard therapy for subacute cutaneous lupus erythematosus (SCLE) includes CS (topical, intralesional, systemic), antimalarials, and other immunosuppressive agents . IVIg may be considered in refractory cases, but more study should be done ( strength of recommendation IIa ).

Level of evidence C

Kikuchi, also called histiocytic necrotizing lymphadenitis, is a rare benign disease. There is little evidence that treatment with IVIg is superior to other anti-inflammatory treatments ( strength of recommendation IIa ).

Adult still disease

Level of recommendation C

Giving the fact that adult still disease responds to CS and biological and anti-tumor necrosis factor (TNF) treatment, there is low-level evidence that IVIg has an additional benefit for treatment of this disease ( strength of recommendation IIa ).

Systemic vasculitis (including GA and MPA)

Level of recommendation B

Immunosuppression with CSs and cytotoxic agents should be used in systemic vasculitis before considering IVIg. There is however some evidence that IVIg might be useful and therefore in refractory cases it may be worth to try ( strength of recommendation IIa ).

Churg–Strauss syndrome

Level of evidence B

CSS is a rare disease. The initial management of CSS consists of high doses of CS. For patients with severe disease or those who are unresponsive to CS, treatment with IVIg was warranted ( strength of recommendation IIa ).

Hepatitis C virus with autoimmune features

Level of evidence B

Infection with hepatitis C virus (HCV) may be associated with a variety of autoimmune phenomena causing a therapeutic dilemma for treatment with interferon alpha (IFN alpha), which stimulates autoimmune symptoms, or with CS, which may lead to an increase of viral load. Treatment with IVIg may act synergistically with IFN alpha, achieving a better response to IFN treatment in patients with chronic HCV associated with autoimmunity ( strength of recommendation IIa ).

Henoch–Schönlein purpura/IgA nephropathy

Level of evidence B

There is some evidence that IVIg treatment may be effective for systemic and kidney disease, rather without sucrose/mannose in the preparation ( strength of recommendation I ).

Mixed connective tissue disease

Level of evidence C

Mixed connective tissue disease (MCTD) is an autoimmune condition which combines features of polymyositis, systemic lupus erythematosus, scleroderma, and dermatomyositis and is thus considered an overlap syndrome. There is scarce evidence that treatment with IVIg helps to improve skin manifestations in MCTD ( strength of recommendation IIa ).

Systemic sclerosis

Level of evidence B

Systemic sclerosis is characterized by hardening and scarring of the skin and inner organs. There is some evidence that treatment with IVIg helps to improve skin and systemic symptoms ( strength of recommendation I ).

Juvenile rheumatoid arthritis

Level of evidence A

There is evidence that IVIg is useful for the treatment of patients with severe chronic JRA; its treatment may help also reduce the need for CS and other immunosuppressive therapy ( strength of recommendation I ).

Rheumatoid arthritis

Level of evidence B

There is hardly any convincing evidence that IVIg benefits patients with RA ( strength of recommendation IIb ).

Sjögren's disease

Level of evidence C

There is some evidence that patients with ataxic sensory neuropathy refractory to immunosuppressive therapy will benefit from IVIg ( strength of recommendation IIa ).

Myopathies (PM, DM, and IBM)

Level of evidence B

In patients with DM and PM that are resistant or partially responsive to conventional therapies, IVIg was effective ( strength of recommendation I ).

Level of evidence A

In IBM, IVIg showed marginal improvements in muscle strength which were nonsignificant and thus were not recommended ( strength of recommendation III ).

Behcet's disease

Level of evidence C

Behcet's disease is a multisystemic disorder presenting with recurrent oral and genital ulcers as well as ocular and central nervous system involvement. The severe cases may respond to systemic CSs, interferon, or anti-TNF therapy. There is some evidence to support IVIg treatment for refractory eye and skin involvement ( strength of recommendation I ; Table 3 ). Table 3 The use of intravenous immunoglobulins in hematological diseases Disease Ref. Study design Intervention including dose and IVIg preparation used Number of patients Results/response Acquired hemophilia [ 92 ] Prospective multicenter study Induction with IVIg (5% Gamimune-N, Miles Inc, Berkeley, CA, USA) 2 g/kg over 2 or 5 days, maintenance with 0.4 g/kg by clinician decision 19 patients with acquired factor VIII inhibitors 8 of 16 assessable patients (50%) had inhibitors reduced in more than 25%; in one third of these responses, concomitant CS treatment may have influenced results [ 93 ] Review of published case reports Different IVIg preparations, dose ranging from 1.6 to 2.8 g/kg over 2–7 days 26 patients with acquired factor VIII inhibitors 16 of 26 patients (62%) had inhibitors reduced in more than 25%; 7 of 26 patients (27%) had clinical benefit [ 93 ] Case series IVIg (Sandoglobulin) 2 g/kg over 5 days 4 patients with acquired factor VIII inhibitors 2 of 4 patients (50%) had inhibitors reduced in more than 25%, but with no clinical benefit; in 2 of 4 patients, the inhibitor reductions were no assessable due to concomitant CS or CP treatment, with clinical benefit in doubt [ 94 ] Review of published case reports Different IVIg preparations and doses; IVIg therapy alone 35 patients with acquired factor VIII inhibitors 30% had inhibitors reduced in more than 25% and clinical benefit [ 95 ] Case series Prednisolone 1 mg/kg per day with IVIg 2 g/kg over 2–5 days 7 patients with acquired factor VIII inhibitors 5 of 7 patients (71%) had inhibitors reduced in more than 25% Acquired hypogammaglobulinemia [ 96 ] RCT crossover study 6 months IVIg (0.3 g/kg per month, Ig-Vena N, Sclavo, Siena, Italy) or placebo, then switch for 12 months and switch again for 6 months 42 CLL patients with hypogammaglobulinemia IVIg treatment yielded more infection free patients at 6 months than placebo (20 vs. 9, p < 0.01) as well as at 12 months (13 vs. 6, p < 0.02) [ 97 ] RCT crossover study 12 months IVIg 0.4 g/kg (Gammagard, Hyland Therapeutic Division, Baxter Healthcare, Glenoak, CA, USA) every 3 weeks or placebo, then switch for 12 months 12 B cell CLL or NHL patients with hypogammaglobulinemia During IVIg treatment, there were more infection-free patients than during placebo administration (6 vs. 1, p = 0.001); in addition, 10 of 12 had lower rates of severe bacterial infection while on IVIg ( p = 0.001) [ 98 ] RCT 18 g IVIg or albumin each 3 weeks for 12 months 42 CLL patients with hypogammaglobulinemia Fewer infections in IVIg-treated (29% vs. 61%, p = 0.04) Fewer severe infections in IVIg-treated (21% vs. 56%, p = 0.02) [ 99 ] RCT IVIg 0.4 g/kg (Gammagard, Baxter Healthcare) or albumin every month for 12 months 82 patients with multiple myeloma 19 serious infection in IVIg-treated compared with 38 in placebo-treated patients ( p = 0.019) No septicemia/pneumonia on IVIg treatment compared with 10 cases in placebo-treated ( p = 0.002) [ 100 ] RCT IVIg (Endobulin, Immuno) 0.4 g/kg or no treatment each month, for 6 months 60 children with acute lymphoblastic leukemia Less infections in IVIg-treated patients [ 101 ] RCT Cefataxim and amikacin with or without IVIg 33 children with acute lymphoblastic leukemia and neutropenic fever Shorter fever duration in IVIg group (5.2 vs. 7.9 days, p < 0.05) Similar neutropenia and hospitalization duration [ 102 ] RCT IVIg (Gammagard Baxter Healthcare Corporation Hyland Division) 0.4 g/kg or placebo every 3 weeks for 12 months 84 CLL patients with hypogammaglobulinemia or a history of infection Overall fewer bacterial infections in the IVIg group (23 vs. 42, p = 0.01) Even more marked difference in those who completed 1 year (14 vs. 36, p = 0.001) [ 103 ] RCT crossover study 6 months IVIg 0.3 g/kg per month (Ig-Vena N, Sclavo, Siena, Italy) or no therapy, then switch for 12 months and switch again for 6 months 25 multiple myeloma patients with hypogammaglobulinemia During IVIg treatment, ten serious infections occurred; during no therapy, phase 30 serious infections occurred, p < 0.002 [ 104 ] Two trials: RCT and RCT crossover study 12 months IVIg 0.4 g/kg every 3 weeks (Gammagard Baxter Healthcare Corporation Hyland Division) or placebo, then switch for 12 months (only in the case of the RCT crossover trial) RCT trial: 81 patients with B cell CLL or low-grade NHL patients with hypogammaglobulinemia RCT trial: less bacterial infections in the IVIg group (23 vs 42, p = 0.01) RCT crossover study: 12 patients with B cell CLL or low-grade NHL patients with hypogammaglobulinemia RCT crossover trial: larger number of patients free of severe infections in the IVIg group (6 vs 1, p = 0.001) Pure red cell aplasia [ 105 ] Case series IVIg 2 g/kg over 5 days 3 pure red cell aplasia patients Good response in all patients [ 106 ] Case series IVIg 2 g/kg (2 patients received Sandoglobulin, Sandoz, Switzerland, 2 patients received Veinoglobulin, Institut Merieux, France) over 5 days 4 patients with red cell aplasia, one idiopathic, another with well-differentiated lymphoma and 2 with B cell CLL Good response in all patients [ 107 ] Case report IVIg 42-year-old male with parvovirus-B19-induced red cell aplasia after stem cell transplantation Good response [ 108 ] Case report IVIg 2 g/kg over 5 days 38 year-old male with parvovirus-B19-induced red cell aplasia after liver transplantation Good response [ 109 ] Case report IVIg (Panglobulin, ZLB Bioplasma, AG, Bern, Switzerland) 2 g/kg over 2 days 14-year-old male with parvovirus-B19-induced red cell aplasia after renal transplantation Good response but development of osmotic sucrose-related renal failure [ 110 ] Case report IVIg 1 g/kg single dose 26-year-old female with parvovirus-B19-induced red cell aplasia after CHOP chemotherapy, rituximab, and radiotherapy Good response [ 111 ] Case report IVIg Relapsing pure red cell aplasia in a patient with B-cell chronic lymphocytic leukemia, refractory to PD and CP Good response [ 112 ] Case report IVIg 4 g/kg over 10 days Patient with parvovirus-B19-induced red cell aplasia after renal transplantation Good response [ 113 ] Case report IVIg 41-year-old male patient with acquired immunodeficiency syndrome and parvovirus-B19-induced red cell aplasia Good response [ 114 ] Case series IVIg 1 to 2 g/kg over 1 to 2 days + maintenance dose 0.4 g/kg each month 8 patients with acquired immunodeficiency syndrome and parvovirus-B19-induced red cell aplasia Good response in 8 of 8 patients, 6 of 8 needed also maintenance IVIg [ 115 ] Case report 0.3 g/kg IVIg (Venilon, Teijin, Osaka) over 6 days 28-year-old female patient with common variable immunodeficiency and parvovirus-B19-induced red cell aplasia Good response [ 116 ] Case report 1 g/kg IVIg 34-year-old male with acquired immunodeficiency syndrome and parvovirus-B19-induced red cell aplasia Good response [ 117 ] Case report 2 g/kg IVIg (Intragam, CSL) over 5 days Male patient with acquired immunodeficiency syndrome and parvovirus-B19-induced red cell aplasia Good response [ 118 ] Case report 2 g/kg IVIg then variable maintenance doses 26-year-old male patient with acquired immunodeficiency syndrome and parvovirus-B19-induced red cell aplasia Good response [ 119 ] Case report IVIg Female patient with chronic idiopathic pure red cell aplasia Good response including 2 uneventful pregnancies during treatment [ 120 ] Case report 2 g/kg IVIg over 5 days 22-year-old female patient with systemic erythematosus lupus and pure red cell aplasia, after failure of CS therapy Good and immediate response [ 121 ] Case report 4 g/kg IVIg (Sandoglobulin) over 10 days, subsequent additional shorter courses and plasmapheresis to due to immune-complex disease 24-year-old female patient with parvovirus-B19-induced red cell aplasia after liver transplantation Late response; it is questionable that the late response is due to IVIg due to the late timing [ 122 ] Case report 2 g/kg IVIg (Sandoglobulin, Sandoz, East Hanover, NJ, USA) over 5 days, subsequent maintenance courses 4-year-old patient pure red cell aplasia Good and long-term response, weaned of blood transfusions [ 123 ] Case report 2 g/kg IVIg over 5 days, subsequent maintenance courses 65-year-old Waldenström's macroglobulinemia patient with parvovirus-B19-induced pure red cell aplasia Good and long-term response, weaned of blood transfusions Acquired von Willebrand syndrome [ 7 ] Prospective noncontrolled study with sequential treatments Desmopressin and factor VIII/von Willebrand factor concentrate where compared to IVIg 2 g/kg over 2 days (Sandoglobulin, Novartis or Ig-Vena Sclavo) 10 MGUS patients with acquired von Willebrand syndrome: 8 had IgG-kappa or lambda, 2 had IgM-kappa Transient increase in plasma von Willebrand factor with desmopressin and factor VIII/von Willebrand factor concentrate; IVIg infusion in IgG-MGUS resulted in a more sustained increase starting on day 4 and returning to preinfusion levels on day 21 [ 94 ] Case series IVIg 9 acquired von Willebrand syndrome patients Good response in 30% [ 124 ] Case report IVIg 0.9 g/kg over 3 days 43-year-old patient with multiple myeloma and gastrointestinal bleeding due to acquired von Willebrand syndrome not responsive to vasopressin Rapid hematological correction after 4 days, bleeding control [ 125 ] Case report IVIg 2 SLE patients with von Willebrand syndrome Good response in one of the 2 patients Aplastic anemia [ 1 ] Case report IVIg 2 patients with idiopathic aplastic anemia No response [ 126 ] Case report IVIg Aplastic anemia patient unresponsive to antithymocyte globulin and CS Good response [ 127 ] Case report IVIg Aplastic anemia due to parvovirus B19 infection in a heart transplant recipient Good response [ 128 ] Case report IVIg (ISIVEN, Instituto Sierovaccinogeno, Italiano ISI SpA) 2 g/kg over 5 days 66-year-old woman with idiopathic aplastic anemia, unresponsive to CS Good response Autoimmune hemolytic anemia [ 129 ] Multicenter noncontrolled study + review of reported cases IVIg (generally Sandoglobulin, Basel, Switzerland, but also Gamimmune N, Cutter Biological, Emeryville, CA, USA; Venilon, Teijin Institute, Tokyo; Sanglopor, Sankyo Institute, Tokyo) 2.5–7 g/kg over 5–7 days 73 patients with autoimmune hemolytic anemia: 36 from multicenter study, 37 from review of published cases 29 patients (39.7%) responded to IVIg: hepatomegaly and low pretreatment hemoglobin were correlated with good response Autoimmune neutropenia [ 130 ] Case series IVIg 0.4–1 g/kg for 5–3 days 20 infants with neutropenia 50% responded after IVIg as compared to 100% with G-CSF and 57% with CS [ 131 ] Case series IVIg 3 g/kg over 3 days 6 infants with neutropenia Fast but transient rise in neutrophils in all Evans' Syndrome [ 132 ] Case series IVIg single or multiple courses + CS 40 patients (children and young adults) Remission in 9/40, transient response in 26/40 (overall improvement in 87%) [ 133 ] Case series IVIg plus CS for either acute hemolysis or thrombocytopenia 5 pediatric patients Transient effect that needed immunosuppressant therapy for maintenance [ 134 ] Case report IVIg 0.4 g/kg for 5 days 3 patients with ES refractory to conventional therapy, including CS and splenectomy in all of the patients, vincristine in 2, and CP in one 2 patients failed to respond, but the third had a clinical remission after IVIg therapy [ 135 ] Case report IVIg 0.4 g/kg for 5 days A patient with steroid resistant ES associated with dermatomyositis IVIg was transiently effective, but a sustain remission was achieved with CP Fetal/neonatal alloimmune thrombocytopenia [ 136 ] Nonrandomized study IVIg, 1 g/kg weekly, or CS given to pregnant women 37 pregnant women with previous pregnancy with alloimmune thrombocytopenia: 27 received IVIg, 10 received CS There was an increase in platelets and no intracranial bleeding in 26% of patients/fetus treated with IVIg as compared with 10% of those treated with CS; in addition, there was no increase in platelets and no intracranial bleeding in 41% of patients/fetus treated with IVIg as compared with 20% of those treated with CS Stem cell/bone marrow transplantation: infections and graft-versus-host disease [ 137 ] RCT 16 weekly doses since 1 week before transplantation of either IVIg (Sandoglobulin, Novartis Pharma, Rueil-Malmaison) 0.05, 0.25, and 0.5 g/kg or placebo 200 patients with allogeneic stem cell transplantation No protection against infections; GVHD and mortality were similar [ 138 ] Randomized trial 64 patients received 0.4 g/kg per week of IVIg (Sandoglobulin, Sandoz, Switzerland); 64 patients received 0.1 g/kg per week of CMV-IgG 128 patients with allogeneic bone marrow transplantation No significant difference in the occurrence or severity of acute or chronic GVHD, infections, or survival [ 139 ] RCT 123 patients received 0.5 g/kg per month of IVIg; 127 patients did not receive IVIg, from the fourth to the 12th month after transplantation 250 patients with allogeneic bone marrow transplantation No significant difference in the occurrence of chronic GVHD, infections, or survival [ 140 ] Randomized trial All received CMV-negative blood products, 25 received IVIg (1 g/kg per week) starting before pretransplant conditioning and then for 17 additional weeks 48 patients after allogeneic BMT, CMV seronegative, which received CMV seropositive or seronegative BMT No difference in the number of bacterial/fungal infections, fewer non-CMV viral infections in the IVIg group (9 vs 15, p = 0.03), less grade ≥II of GVHD in the IVIg group, p = 0.04 [ 141 ] Multicenter RCT IVIg (Venoglobulin S 5%, Alpha Therapeutic Corporation, LA, CA, USA), 0.1, 0.25, or 0.5 g/kg, started 2 days before transplant, continued weekly for 90 days and then monthly until 1 year after transplant 618 allogeneic bone marrow transplant recipients Acute GVHD occurred in 39% (80/206) in the 0.1-g/kg group, 42% (88/208) in the 0.25-g/kg group, 35% (72/204) in the 0.5 g/kg group No difference in incidence of chronic GVHD, infection, interstitial pneumonia, type of infection, relapse of hematological malignancy or survival [ 142 ] Randomized trial IVIg (Sandoglobulin, Sandoz Pharmaceuticals, East Hanover, NJ, USA) 0.5 g/kg per week administered since the beginning of the cytotoxic therapy or nothing 170 autologous bone marrow transplant patients IVIg did not reduce infection of infection-related death [ 143 ] RCT IVIg (Gamimune N, Cutter Biological, Berkeley, CA, USA) 0.5 g/kg per week to day 90, then 0.5 g/kg per month to day 360 after transplantation or nothing 382 patients after bone marrow transplantation Lower risk of gram-negative septicemia ( p = 0.0039) in IVIg and of local infection ( p = 0.029) No difference in survival; there was a risk reduction in the incidence of acute GVHD ( p = 0.0051) Decrease in deaths due to transplant-related causes after transplantation of HLA-identical marrow ( p = 0.023) Hemolytic disease of the newborn [ 144 ] Meta-analysis of 3 not-blinded RCT IVIg and phototherapy or phototherapy alone 189 patients Less use of exchange transfusion in the IVIg group: when given for prophylaxis RR = 0.21 ( p < 0.001), when given as treatment RR = 0.36 ( p < 0.006) [ 145 ] Meta-analysis of 3 RCTs IVIg and phototherapy or phototherapy alone 189 patients Overall less use of exchange transfusion in the IVIg group: RR = 0.28 ( p < 0.00001) Hemolytic transfusion reaction [ 146 ] Case series IVIg (Endobulin HT, Immuno AG, Vienna, Austria) 0.4 g/kg (single infusion) was administered within 24 h of transfusion 5 patients are known to develop non-ABO post-transfusional hemolytic reactions No transfusion reaction and sustained increase in hematocrit [ 147 ] Case report IVIg (Sandoglobulin) 75 gr. over 3 days + CS Rh-negative patient with anti-Jk, anti-K, and anti-Kp Increase in hemoglobin, no evidence for hemolysis Hemolytic transfusion reaction in sickle cell disease [ 148 ] Case reports IVIg 2 g/kg over 5 days + high-dose MP 2 patients with sickle cell disease who developed a hemolytic reaction after compatible blood transfusion Increase in hemoglobin and reticulocytes [ 149 ] Case reports IVIg 2 g/kg over 5 days + high-dose MP 2 patients with sickle cell disease who developed a hemolytic reaction after compatible blood transfusion Increase in hemoglobin and reticulocytes [ 150 ] Case report IVIg (Sandoglobulin, 1 g/kg per day for 1 to 2 days) + CS Patient with sickle cell disease who developed a hemolytic reaction after compatible blood transfusion Increase in hemoglobin and reticulocytes Hemolytic uremic syndrome [ 151 ] Case control study IVIg 0.4–2.4 g/kg (Gamimune N, Cutter Etobicoke, Ontario, Canada) over 1–6 days (0.4 g/kg per day) 18 children with postdiarrhea hemolytic uremic syndrome, 9 received IVIg No benefit of IVIg treatment [ 152 ] Case control study IVIg 2 g/kg (Sandoglobulin) over 5 days in 8 patients, FFP in 12 patients, no treatment in 23 patients 43 children with hemolytic uremic syndrome; 8 received IVIg Improvement in platelet count against FFP ( p < 0.05) and against no treatment ( p < 0.01) Thrombotic thrombocytopenic purpura [ 153 ] Case series IVIg 0.4 g/kg per day, from 1 to 20 infusions; these patients were also treated with CS, also PP in 15 patients 17 patients with thrombotic thrombocytopenic purpura 10/17 (58.8%) patients had remission, 8/17 (47%) complete remission [ 154 ] Case control study IVIg 2 g/kg over 5 days in 29 patients only; all the patients received PP and CS 44 patients with thrombotic thrombocytopenic purpura No benefit of IVIg treatment Heparin-induced thrombocytopenia [ 155 ] Case series IVIg (Sandoglobulin in 2 cases, Octagam in one case) 2 g/kg over 2 days 3 patients with heparin-induced thrombocytopenia Increase in platelet count [ 156 ] Case report IVIg 51-year-old woman with heparin-induced thrombocytopenia and pulmonary embolism Increase in platelet count starting 20 h after first IVIg infusion HIV-associated thrombocytopenia [ 157 ] RCT crossover study Weekly IVIg (Polygam) courses of 2 g/kg over 2 days or normal saline, for 4 weeks, then crossover 12 HIV patients with HIV-related thrombocytopenia IVIg consistently and reproducibly raised platelet count after infusion; no patient with placebo did so ( p < 0.00003) Acute immune thrombocytopenic purpura [ 158 ] RCT not blinded IVIg 2.1 g/kg over 3 days (Gammagard SD, Baxter Bioscience, Glendale, CA) or high-dose MP 15 mg/kg per day for 3 days Acute immune thrombocytopenic purpura adult patients, 56 randomized to IVIg, 60 to MP Faster response and higher platelet counts in the IVIg group ( p = 0.006) [ 159 ] RCT nonblinded IVIg 2 g/kg over 5 days (7 patients), PD 1 mg/kg per day (13 patients) or both IVIg and PD (12 patients) 32 acute immune thrombocytopenic purpura adult patients No difference in response rates or in requirements for splenectomy or in bleeding [ 160 ] RCT nonblinded IVIg 2 g/kg over 2 days (19 patients) or PD with starting dose of 4 mg/kg per day and then tapering until discontinuation by day 21 (18 patients) or no therapy (16 patients) 53 children with acute immune thrombocytopenic purpura and less than 20,000 platelets per microliter Both IVIg- and PD-treated children reached platelet counts over 50,000 per microliter faster than children not treated ( p < 0.001) Median time to reach more than 50,000 platelets per microliter was lower in IVIg group (2 days) than in PD group (4 days), p < 0.001 [ 161 ] Partially randomized trial; patient's family chose no treatment or treatment (IVIg or CS upon randomization) IVIg 1.6 g/kg over 2 days (12 patients) or MP with starting dose of 30 mg/kg per day for 3 days and then 20 mg/kg per day for 4 days (12 patients) or no therapy (26 patients) 50 children with acute immune thrombocytopenic purpura and less than 20,000 platelets per microliter Both IVIg- and MP-treated children reached platelet counts over 20,000 per microliter and 50,000 per microliter faster than children not treated, p < 0.01 Immune thrombocytopenic purpura in HIV [ 162 ] Controlled clinical trial IVIg 2 g/kg of IVIg over 2 days, followed by IVIg 1 g/kg on day 15 14 patients with HIV-related thrombocytopenia (median platelet count 17,000/mm 3 ) All achieved resolution of their bleeding by day 8, but this was temporary [ 163 ] Controlled clinical trial IVIg 0.04 g/kg per week during 5 weeks 13 thrombocytopenic AIDS patients All patients responded in the first week but only 4 were responders after 3 months Chronic immune thrombocytopenic purpura [ 164 ] Prospective noncontrolled trial IVIg 2 g/kg over 2 or 5 days (BT681m, Biotest Pharma GmbH, Dreieich, Germany) in accordance to randomization, followed for 28 days 24 chronic immune thrombocytopenic purpura adult patients 91.7% of patients underwent a fast raise (in 2–5 days) of platelet count over 50,000 per microliter; at the end of the 28 days of follow-up, half of the patients had still platelet count over 50,000 per microliter [ 165 ] Prospective noncontrolled trial Induction with IVIg 1 or 2 g/kg (Biotransfusion, Roissy, France) over 2 days and 6 more maintenance infusions of IVIg 1 g/kg starting when platelets fell below 50,000 per microliter and then every 2 to 3 weeks unless platelets are over 150,000 per microliter or response is exhausted 20 chronic immune thrombocytopenic purpura adult patients Initial response in all 18 evaluable subjects, 13 complete (>150,000 per microliter), 5 partial (>50,000 per microliter); no difference between both induction doses; maintenance: at 90-day failure in 61% (11 of 18), partial response (>50,000 per microliter in 2 of 18, 11%) and complete response (>150,000 per microliter in 5 of 18, 28%) Posttransfusional purpura [ 166 ] Case series IVIg 17 patients with severe thrombocytopenia after blood transfusion In 16 patients, normal platelet counts were reached within days; 5 patients relapsed and again had a good response to new IVIg administration [ 167 ] Case series IVIg 0.4 g/kg per day, for 2–10 days 5 patients with severe thrombocytopenia after blood transfusion Immediate raise in platelet count and cessation of bleeding in 4 of 5 patients (80%) [ 168 ] Case series IVIg, variable doses ranging from 1 to 2 g/kg per day 3 patients with thrombocytopenia after blood transfusion Good response in 2 of 3 patients Hemophagocytic syndrome [ 169 ] Case series IVIg 6 renal transplant patients with hemophagocytic syndrome Good response in all the cases [ 170 ] Case series IVIg 7 children with hemophagocytic syndrome treated with IVIg only 3 of 7 (43%) survived [ 171 ] Case series IVIg 2 g/kg over 2 days in one case, over 5 days in the other 2 cases of EBV-associated hemophagocytic syndrome treated with IVIg only 2 of 2 (100%) survived [ 172 ] Case series IVIg 8 children with infection-associated hemophagocytic syndrome treated with IVIg 0 of 8 (0%) survived [ 173 ] Case series IVIg 1 g/kg per day for 1 or 2 days 3 children with infection-associated hemophagocytic syndrome treated with IVIg 3 of 3 (100%) survived [ 174 ] Case report IVIg A healthy patient with CMV-related hemophagocytosis Symptoms and laboratory abnormalities improved dramatically after the onset of the treatment POEMS syndrome [ 175 ] Case report 2 courses of IVIg 0.4 g/kg per day for 5 days, separated by 3 weeks, adjunctive to radiotherapy 49-year-old patient with rapidly progressive polyneuropathy associated with osteosclerotic myeloma After 2 courses of IVIg improvement of respiratory and sexual function and gate, disappearance of numbness; doing well after 1 year [ 176 ] Case report IVIg 0.4 g/kg per day for 4 (case 1) or 5 days (case 2) adjunctive to prednisolone 30–50 mg/day A 55-year-old man (case 1) and a 43-year-old woman (case 2) with late-stage POEMS No change in motor and sensory impairment; case 1 continued to deteriorate and died after 6 months due to sepsis and DIC [ 177 ] Case report IVIg (one course) A patient with POEM and Castleman's disease No effect Diffuse B cell posttransplant lymphoproliferative disorder [ 178 ] Case report IVIg 0.5 g/kg every 15 days for 4 months (case 1) and for 12 and 7 months, respectively (case 2) adjunctive with IFN alpha (2 × 10 6 IU SC 3 times a week) 2 patients with diffuse B cell posttransplant lymphoproliferative disorder Complete disappearance of all lesions after 3 months of the therapy in case 1 and after 7 months in case 2, remission for 47 months and 33 months, respectively POEMS syndrome polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes

Acquired hemophilia

Level of evidence B

There is weak evidence that IVIg is useful in the treatment of acquired hemophilia. IVIg may be tried in the case in which CS and cytotoxic agents fail or when facing an emergency situation as an additional therapy IVIg ( strength of recommendation IIa ).

Acquired hypogammaglobulinemia

Level of evidence A

There is strong evidence that IVIg is of benefit in reducing the number and severity of infections in patients with acquired hypogammaglobulinemia in the context of hematological malignancy ( strength of recommendation I ). While this is true, both cost and the potential of adverse effects, most prominently acute renal failure and thromboembolic phenomena [ 3 – 5 ], prevent a clear-cut recommendation for the use of IVIg in acquired hypogammaglobulinemia. With this in mind, IVIg may be recommended at the replacement dose of 400 mg/kg each 3 to 4 weeks in cases in which severe or recurrent infections have occurred.

Pure red cell aplasia

Level of evidence C

Pure red cell aplasia may be immune-mediated due to a background neoplasia, most frequently hematologic, or due to an immune disease or as an immune response triggered by drugs. It may also occur secondary to parvovirus B19 infection which may also lead to aplastic anemia. Treatment of the causative disease is the most important issue. Weak evidence supports the use of IVIg in pure red cell aplasia. IVIg may however be used in the case in which first-line therapy (i.e., CS and immunosuppressive drugs) fails to achieve a remission ( strength of recommendation IIa ). IVIg is first-line therapy in immunosuppressed hosts in which infection with parvovirus B19 results in pure red cell aplasia.

Acquired von Willebrand syndrome

Level of evidence B and C

According to Federici and colleagues [ 6 ], 48% of the cases of acquired von Willebrand syndrome are associated with lymphoproliferative diseases, 15% with myeloproliferative disorders, and 21% with cardiovascular diseases. In another paper, Federici and colleagues [ 7 ] claim that 33% of the reported cases are associated with a monoclonal gammopathy of uncertain significance. Then, the detection and specific treatment of the underlying disease is as important as the immediate therapy of the coagulation disorder. In accordance to the scant existing evidence of IVIg therapy in this disorder, IVIg should be used in cases of standard therapy (desmopressin and factor VIII/von Willebrand factor concentrate) failure and in urgent situations as an addition to such therapy ( strength of recommendation IIb ). IVIg may also be used in the preparation for surgery.

Aplastic anemia

Level of evidence C

While idiopathic aplastic anemia can be transient as in the case of parvovirus-B19-induced bone marrow depression, idiopathic aplastic anemia should first be treated with immunosuppressive drugs like CS or cyclosporine or with antithymocyte or antilymphocyte immunoglobulins as well as supportive blood components transfusions. Stem cell transplantation is always the alternative in the case of failure of the aforementioned treatments. Due to the low level of evidence of IVIg for the treatment of idiopathic aplastic anemia, we cannot recommend its liberal use but it may be tried in the case of treatment failure, before stem cell transplantation is performed ( strength of recommendation IIb ).

Autoimmune hemolytic anemia

Level of evidence B

Immunosuppression with CS and then cytotoxic agents should be used in autoimmune hemolytic anemia before considering IVIg. There is however some evidence that IVIg might be useful and therefore in refractory cases before considering splenectomy it may be worth a try ( strength of recommendation IIb ).

Autoimmune neutropenia

Level of evidence C

Although immune neutropenia may also be an adverse effect resulting from IVIg treatment as have been published elsewhere [ 8 ], IVIg has been used to treat immune neutropenia. The evidence is weak and responses are not as good as those with CS and granulocyte colony-stimulating factor ( strength of recommendation IIb ).

Evans’ syndrome

Level of evidence C

Evans’ syndrome is usually a therapy-resistant condition that has been treated combining CS, IVIg, and immunosuppressive therapy. Although convincing evidence is lacking for the use of IVIg in view of the severity and the refractory nature of several cases of Evans’ syndrome, IVIg may be considered among the treatment options generally together with CS with or without immunosuppressive therapy ( strength of recommendation IIb ).

Fetal/neonatal alloimmune thrombocytopenia

Level of evidence B

The only study comparing IVIg against other treatment (CS), although nonrandomized, suggests that IVIg raises the platelet number and prevents intracranial bleeding in a significant percentage of treated patients. The level of evidence is low, but the alternatives for prenatal treatment of fetuses at risk are not better and the risks involved are huge ( strength of recommendation IIb ).

Stem cell/bone marrow transplantation

Level of evidence A

Strong evidence denies any benefit from the use of IVIg around stem cell/bone marrow transplantation, both from the infectious or from the graft-versus-host disease point of views ( strength of recommendation III ).

Hemolytic disease of the newborn

Level of evidence A

There is clear evidence for the use of IVIg when facing newborn hemolysis as it reduces the need of plasmapheresis (PP) therapy ( strength of recommendation I ).

Hemolytic transfusion reaction

Level of evidence C

There is no reliable evidence to recommend the use of IVIg to prevent or to treat hemolytic transfusion reactions ( strength of evidence IIb ).

Hemolytic transfusion reaction in sickle cell disease

Level of evidence C

Apart from two papers reporting two cases and another case, there is no evidence to recommend the use of IVIg either to prevent or to treat hemolytic transfusion reactions in sickle cell patients, specially taking into consideration the additional risk of thrombosis due to a change in the rheologic properties of the blood after IVIg infusion ( strength of recommendation IIb ).

Hemolytic uremic syndrome

Level of evidence B

There is conflicting evidence that IVIg benefits patients with hemolytic uremic syndrome ( strength of recommendation IIb ).

Thrombotic thrombocytopenic purpura

Level of evidence B

There is no evidence that IVIg benefits patients with thrombotic thrombocytopenic purpura ( strength of recommendation III ).

Heparin-induced thrombocytopenia

Level of evidence C

There is low-level evidence that IVIg is useful for this disease. On the other hand, thromboembolic phenomena, which are part of the heparin-induced thrombocytopenia clinical picture, might be enhanced by the rheologic blood changes after IVIg infusion. Therefore, IVIg should not be generally recommended for this disease ( strength of recommendation IIb ).

HIV-associated thrombocytopenia

Level of evidence B

Evidence comes only from one crossover randomized placebo-controlled trial which supports the use of IVIg in HIV-associated thrombocytopenia, especially when platelet count is very low or the risk of bleeding is high ( strength of recommendation IIa ).

Acute immune thrombocytopenic purpura

Level of evidence A

Since Imbach’s observation [ 1 ], acute ITP has been the prototype of IVIg-responsive immune disease. There is consistent evidence that IVIg is beneficial in children with ITP ( strength of recommendation I ). Notwithstanding this, CS therapy is still the first-line treatment for ITP, and single-dose anti-D immunoglobulin [ 9 , 10 ] is a [ 8 ] good alternative for Rh-positive patients. IVIg should be considered when there is bleeding or when the bleeding risk is high or upon failure of other treatments. In adult acute ITP patients, there is no placebo-controlled RCT, but when compared with CS IVIg induces a faster response. Again, CS is the first-line treatment for adults but IVIg may be given in severe or refractory cases. There is weak evidence that IVIg can improve mother and fetal prognosis in pregnancy. IVIg may be used when a fast correction in platelet number is needed.

Immune thrombocytopenic purpura in HIV

Level of evidence B

By the merits of its own research, IVIg may be considered to treat ITP in the context of HIV. Although no hard evidence exists due to the fact that this particular group of patients has not been investigated as well as has non-HIV-related ITP, it will be hard to argue that the recommendation of the latter may not be extended to HIV-related ITP ( strength of recommendation I ).

Chronic immune thrombocytopenic purpura

In chronic ITP, IVIg has so far not demonstrated a plausible benefit. Only prospective noncontrolled trials are available and we found only one evaluating maintenance IVIg for chronic ITP, in which the overwhelming majority of patients had a recrudescence of thrombocytopenia in spite of a good initial response to IVIg (level of evidence and strength of recommendation B-IIb). A small number of patients benefited and therefore IVIg might be tried in drug refractory cases of chronic ITP in which there is a contraindication for splenectomy.

Posttransfusional purpura

Level of evidence C

Series of patients treated with fast response to IVIg suggest a benefit of IVIg treatment in posttransfusional purpura, although with low-level of evidence. In the context of a patient with severe risk to bleeding or actual bleeding, IVIg can be used if the diagnosis of posttransfusional purpura is made (strength of recommendation IIb).

Hemophagocytic syndrome

Level of evidence C

Hemophagocytic syndrome is a severe reaction leading to high mortality. Inconsistent and low-level evidence do not warrant a clear-cut recommendation of IVIg for this syndrome. However, due to the lack of effective and standardized treatment in an otherwise highly lethal disease, IVIg may be used along with other therapies like monoclonal antibodies, CS, cytotoxic drugs, and support measures ( strength of recommendation IIb ).

POEMS

Level of evidence C

There are only anecdotal reports, both showing benefit and lack of benefit. There is no evidence that IVIg has a beneficial effect on polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes ( strength of recommendation IIb ).

Diffuse B cell posttransplant lymphoproliferative disorder

Level of evidence C

There is no convincing evidence that IVIg has any beneficial effect in this disease ( strength of recommendation IIb ; Table 4 ). Table 4 The use of intravenous immunoglobulins in infectious diseases Disease Ref. Study design Intervention including dose and IVIg preparation used Number of patients. Results/response Cytomegalovirus (CMV) [ 179 ] Controlled trial IVIg 0.25 g/kg weekly for 8 weeks, starting on the operative day 40 renal transplanted patients with negative serology for CMV Effective prophylaxis, associated with excellent 1-year allograft survival Human immunodeficiency virus (HIV) child infection [ 180 ] RCT IVIg 0.4 g/kg or placebo (0.1% albumin) every 28 days 372 symptomatic children infected with HIV Significant reduction in serious infections ( p = 0.01) and hospitalizations ( p = 0.03), in the IVIg group only for those entering treatment with CD4+ lymphocyte ≥200; no effect on mortality [ 181 ] Controlled trial IVIg (Gamimune-N, Miles Pharmaceutical Co.), 0.2 g/kg monthly for 1 year 135 symptomatic and asymptomatic children with perinatal HIV Significant reduction in the frequency of bacterial infections in the symptomatic group HIV-associated thrombocytopenia—see hematology section Malaria [ 182 ] RCT All were treated with IV quinine dihydrochloride; in addition, patients were randomized to receive either IVIg, 0.4 g/kg over 3 h, or placebo 31 children with Plasmodium falciparum parasitemia and coma Of 16 patients receiving immunoglobulin, 5 (31%) died, and 5 survivors had neurological sequelae; of 15 patients receiving placebo, one (7%) died and 2 had sequelae (trial was stopped) [ 183 ] Controlled trial IVIg was prepared from 180 donors after infection screening; 6 patients were treated with a 0.1-g/kg dose given over 3 days, one with a single 0.02-g/kg dose, and one with a single 0.02-g/kg dose 8 Thai patients with P . falciparum parasitemia Clearance of parasites and symptoms was as fast as or faster than with drugs Postpolio syndrome (PPS) [ 184 ] Multicentered RCT 90 g of IVIg during 3 days, repeated after 3 months 142 patients: 73 with IVIg and 69 placebos Mild improvement in median muscle strength ( p = 0.03), vitality ( p = 0.04), no change and quality of life ( p = 0.3) [ 185 ] RCT Patients were randomized to IVIg, 2 g/kg, or placebo 20 patients with PPS No effect was seen with IVIg treatment on muscle strength and fatigue; however, IVIg patients reported significantly less pain 3 months after treatment [ 186 ] Open clinical trial 90 g of IVIg (30 g daily for 3 days) 14 patients with PPS Significant improvement in the quality of life, no change in muscle strength and physical performance Sepsis [ 187 ] Meta analysis of RCT's from PubMed Different preparations of relatively low doses of IVIg for severe sepsis, mostly surgical patients with gram-negative infections 14 RCTs published between 1988 and 2006 were included Significant but heterogenic reduction in mortality associated with use of IVIg ( p < 0.0005); this result was not confirmed when only high-quality studies were analyzed West Nile Virus (WNV) [ 188 ] Case report 0.4 g/kg IVIg preparation from donors that contained a high titer of anti-WNV antibodies (1:1,600) 42-year-old male lung-transplant recipient with severe WNV encephalitis Complete disappearance of signs and symptoms within 48 h [ 189 ] Case report IVIg 0.4 g/kg for 5 days (Omr-IgG-am, Omrix Biopharmaceutical Ltd., Tel Hashomer, Israel) 70-year-old with chronic lymphatic leukemia and coma due to WNV Level of consciousness returned to normal over 5 days Prophylaxis for infections (in intensive care units (ICU)) [ 190 ] RCT Patients received standard IVIg, 0.4 g/kg, hyperimmune globulin (HG), 0.4 g/kg, or placebo, weekly, for a maximum of 4 doses 329 postsurgical patients admitted to the surgical ICU Significantly lower infections and hospital days in the IVIg group vs. placebo or HG ( p = 0.003); no lesser mortality/shock [ 191 ] RCT Patients received IVIg (36 g) versus 0.03% albumin 150 trauma patients in ICU ventilated for >24 h Decreased overall incidence of infection ( p = 0.02) and antibiotic need in IVIg group [ 192 ] RCT Ten patients received IVIg and ten albumin 20 patients with extensive thermal injury No statistically significant difference was found between mortality rates of the groups [ 193 ] RCT 18 received IVIg, 0.4 g/kg, and 14 placebo within 48 h of admission 33 children (mean age, 6.67 years) with severe head injuries No effect on the incidence of secondary infections [ 194 ] RCT Within 12 h of ICU admission, 1 g/kg of IVIg or human albumin divided over 4 days 39 trauma patients in an ICU No difference in overall infection rates, but fewer pneumonias ( p = 0.003) and non-catheter-related infections ( p = 0.04); no difference in ICU length of stay or antibiotic use [ 195 ] RCT Patients were randomly assigned to either 20 g IVIg or saline 40 postoperative open-heart surgery patients with cutaneous anergy preoperatively Infection incidence 5% in IVIg versus 43% placebo ( p = 0.007) Prophylaxis for infections (in immune-compromised patients) [ 142 ] RCT 82 received IVIg weekly, 0.5 g/kg, from the initiation of cytotoxic therapy to the resolution of neutropenia and 88 were untreated controls 170 neutropenic patients undergoing BMT or severe myelosuppressive therapy The use of IVIg did not prevent infection; fewer deaths occurred among controls due to a higher incidence of fatal hepatic veno-occlusive disease in patients receiving IVIg [ 196 ] RCT Monthly IVIg 0.4 g/kg or placebo for 1 year 82 patients with stable multiple myeloma Less infection sepsis in the IVIg group ( p = 0.002) Necrotizing fasciitis (NF) [ 197 ] Controlled trial 16 were treated with ≥1 mg/kg of IVIg; all were treated with antibiotics and debridement 20 patients with NF No difference in case fatality [ 198 ] Controlled trial Patients were treated with effective antimicrobials, high-dose IVIg; surgery was either not performed or only limited exploration was carried out 7 patients with severe NF All patients survived [ 199 ] Controlled trial Patients that had hypotension and multiorgan failure were treated with a single dose of IVIg 50 g in addition to antibiotics 11 patients with toxic shock syndrome with or without NF Ten patients were fully recovered [ 200 ] Case report Patient declined on antibiotic therapy and was treated with IVIg, 0.4 g/kg (Omr-IgG-am 5% IV, Omrix, Israel) A renal transplant lupus patient with NF A marked improvement in patient's condition on the next day Recurrent otitis media (OM) [ 201 ] RCT IVIg or placebo 22 otitis-prone children, 1–4 years old No significant difference in the frequency of OM attacks or other respiratory tract IVIg group [ 202 ] Controlled trial IVIg 9 children with recurrent sinopulmonary infections which failed to improve after antibiotic Tx Significant decrease in the episodes of sinusitis and OM Varicella (transmission prevention) [ 203 ] Controlled trial IVIg prophylaxis (single-dose 0.5 g/kg) administered soon after birth or postnatal contact, either alone or with IV acyclovir 24 newborns whose mother had a varicella rash within 14 days before and after delivery Treatment with IVIg + acyclovir effectively prevented perinatal varicella [ 204 ] Controlled trial IVIg 0.04 to 0.045 g/kg per day for 5 to 9 days was given soon after birth, along with acyclovir 5 infants whose mothers had varicella Some had a mild–moderate transient rash but none had constitutional symptoms Varicella (pulmonary disease) [ 205 ] Case report IVIg and IV acyclovir 2 cases of varicella infection complicated by severe pulmonary involvement previously healthy adults Gradual clinical improvement after administration [ 206 ] Case report IVIg, 2.5 g every 12 h, with IV acyclovir and ABx A healthy adult with severe respiratory failure due to varicella pneumonia Gradual clinical improvement after administration [ 207 ] Case report IVIg and IV acyclovir 32-year-old patient with varicella and ARDS Quick improvement [ 208 ] Case report Patient was mechanically ventilated and treated with IVIg and acyclovir 26-year-old with ARDS secondary to varicella pneumonia Quick improvement Varicella (complicated with ITP) [ 209 ] Case report IVIg ITP in a 3-year-old girl with an active varicella infection Drastically improved bleeding and active varicella infection [ 210 ] Case report IVIg, 0.4 g/kg per day for 3 days, and acyclovir 40-year-old with bleeding due to varicella-related ITP The platelet counts increased to 254,000 per microliter over the next 5 days, and the skin rashes associated with varicella subsided within a week

Cytomegalovirus

Level of evidence B

IVIg is not used for the treatment of CMV infection but may be helpful in treatment of hemophagocytic syndrome related to CMV and other viruses (see hematology section); there is some evidence for its effectiveness in preventing seroconversion in transplant patients who are immunosuppressed ( strength of recommendation I ).

Human immunodeficiency virus

Level of evidence B

IVIg can reduce infections in children with perinatal HIV but has not been proven to reduce mortality ( strength of recommendation IIa ).

Malaria

Level of evidence B

No evidence for the effectiveness of IVIg in the treatment in malaria exists ( strength recommendation III ).

Postpolio syndrome

Level of evidence A

Postpolio syndrome (PPS) typically affects survivors of poliovirus infection, 15–20 years after the original infection, with fatigue, muscular weakness, and pain. There are two RCTs demonstrating some inconsistent evidence for the effectiveness of IVIg treatment on quality of life, pain, and muscle strength in patients with PPS ( strength of recommendation IIa ).

Sepsis

Level of evidence A

Sepsis is a life-threatening condition, resulting mainly from the patient’s immune response to a severe infection. Significant but heterogenic reduction in mortality with IVIg treatment in septic patients was demonstrated in a meta-analysis of 14 RCTs. These results were not confirmed when only high-quality studies were analyzed ( strength of recommendation IIa ).

West Nile

Level of evidence C

Infection with West Nile virus can cause fatal encephalitis in immunosuppressed and elderly patients, in which case effective treatment is lacking. The effectiveness of IVIg in these situations is supported by a few case reports and may be considered ( strength of recommendation IIa ).

Infection prophylaxis—in intensive care units

Level of evidence A

Treatment with IVIg has not proven to reduce infectious-related mortality in postsurgical patients, but there is inconsistent evidence that IVIg reduces ICU-related infections and hospital stay in these patients ( strength of recommendation IIa ).

Infection prophylaxis—in immune-compromised patients

Level of evidence A

There is conflicting evidence regarding the usefulness of IVIg treatment for these patients. It should be taken into consideration that patients treated with IVIg after bone marrow transplantation (BMT) may have a higher incidence of fatal hepatic veno-occlusive disease ( strength of recommendation IIa ).

Necrotizing fasciitis

Level of evidence B

Necrotizing fasciitis is caused by deep-skin infection with bacteria, mainly group A streptococcus. The mainstay of nuclear factor treatment is prompt surgical exploration and antibiotic therapy. IVIg might have additional benefit to antibiotic therapy for treatment of patients who refuse surgery or are not surgical candidates. ( strength of recommendation IIa ).

Recurrent otitis media

Level of evidence B

There is weak evidence that IVIg is useful in the treatment of recurrent otitis media ( strength of recommendation IIb ).

Varicella

Level of evidence B

Some evidence that IVIg is effective in preventing perinatal transmission of varicella. IVIg may also be used for treatment adults with severe respiratory failure due to varicella pneumonia ( level of recommendation IIa ; Table 5 ). Table 5 The use of intravenous immunoglobulins in gyneco-obstetric diseases Disease Ref. Study design Intervention including dose and IVIg preparation used Number of patients Results/response Perinatal hemochromatosis [ 211 ] Case–control study; previous patients' pregnancies used as their own controls IVIg 1 g/kg weekly since week 18 15 patients (16 pregnancies) with previous pregnancies resulting in perinatal hemochromatosis Good outcome (survived with or without medical therapy) in 15 gestations treated with IVIg; in historical controls of the same mothers, 2 pregnancies had good outcome and 13 had poor outcome (fetal or neonatal death, or liver failure necessitating liver transplantation), p = 0.0009 Recurrent pregnancy loss excluding antiphospholipid syndrome [ 212 ] Meta-analysis IVIg 442 women with recurrent spontaneous miscarriages (at least 3) from eight RCTs; secondary recurrent miscarriages are defined as those in women that had at least a previous successful birth No significant difference ( p = 0.21) between women with primary recurrent miscarriages treated with IVIg or without; however, there was a significant improvement of live births when IVIg was given to women with secondary recurrent miscarriages ( p = 0.03) [ 213 ] Meta-analysis IVIg versus placebo or no treatment 303 women with idiopathic recurrent abortions from 8 RCTs No benefit of IVIg on recurrent pregnancy loss [ 214 ] Meta-analysis IVIg 246 women with recurrent spontaneous miscarriages (at least 2) from 5 RCTs; secondary recurrent miscarriages are defined as those in women that had at least a previous successful birth No significant difference between women with primary recurrent miscarriages treated with IVIg or without; not enough patients to conclude something about women with secondary recurrent miscarriages but there was a trend towards improvement [ 215 ] RCT 29 women received IVIg, 29 placebos; IVIg was administered from weeks 5–10 weekly at 0.8 g/kg every week, from weeks 10–20 at 0.8 g/kg every 2 weeks and from weeks 20–26 at 1 g/kg every 2 weeks; no IVIg as given after week 26 58 women with recurrent spontaneous miscarriages (at least 4); secondary recurrent miscarriages are defined as those in women who had at least a previous pregnancy that progressed to week 26 or more No benefit in primary recurrent miscarriages but a trend towards improvement among women with secondary recurrent miscarriages [ 216 ] Meta-analysis IVIg in 125 patients, 115 received placebo 240 women with recurrent spontaneous miscarriages No benefit of IVIg [ 216 ] RCT IVIg (Gammonativ) 20 g every 3 weeks, 5 courses after confirmation of pregnancy 41 women with recurrent spontaneous miscarriages No benefit of IVIg neither for women with primary or secondary recurrent miscarriage [ 217 ] RCT 22 patients received IVIg (Sclavo) 50 g over 2 days upon confirmation of pregnancy (weeks 5–7) and again 25 g 3 weeks later 46 women with recurrent spontaneous miscarriages No benefit of IVIg [ 218 ] RCT 47 patients received IVIg 0.5 g/kg every month starting up to 4 months before pregnancy and until weeks 28–32 of pregnancy; 48 patients received placebo 95 women with recurrent spontaneous miscarriages (2 or more) More live births in women receiving placebo ( p = 0.04) [ 219 ] RCT IVIg (Nordimmun, Novo-Nordisk, Gentofte, Denmark) 25–40 g per dose according to patient weight every 2 weeks until week 34 of pregnancy or placebo 34 women with secondary recurrent spontaneous abortion (subsequent to a birth or including at least one second trimester miscarriage) More live births but not statistically significant in the IVIg group (52.9% against 29.4%) [ 220 ] RCT IVIg initial dose 30 g, then 20 g every 3 weeks until week 25 (Verum, Immuno GmbH, Heidelberg, Germany) or placebo 64 women with primary recurrent spontaneous abortion No benefit of IVIg Recurrent pregnancy loss in antiphospholipid syndrome [ 221 ] Meta-analysis IVIg given in addition to heparin and aspirin 58 women with recurrent miscarriages due to antiphospholipid syndrome in 2 RCTs Increased risk of pregnancy loss or premature birth in the group receiving IVIg [ 222 ] Randomized trial 21 women received IVIg (IgVENA N; Sclavo, Siena, Italy) at the dose of 0.8 g/kg over 2 consecutive days as initial dose followed by 0.4 g/kg each month up to week 31; 19 women received aspirin 75 mg/day up to week 34 + heparin 5,700 IU/day up to week 37 40 women with at least 3 abortions due to antiphospholipid syndrome were treated since conception with IVIg or heparin + aspirin More live births (84% against 57%, not significant difference) in the aspirin + heparin group ( p = 0.06) [ 223 ] RCT IVIg 2 g/kg (Gamimune-N, Bayer Corporation, West Haven, CT, USA) over 2 days every 4 weeks through 36 weeks’ gestation 16 pregnant women (no more than 12 weeks' gestation) with recurrent miscarriages due to antiphospholipid syndrome received low-dose aspirin and heparin and received random IVIg or placebo No benefit of IVIg [ 224 ] Prospective two-center trial study 29 were treated with PD and LDA; 53 received IVIg 0.5 g/kg (Alphaglobin, Grifols International, Pisa, Italy) for 2 consecutive days, once a month from the 5th to the 32nd week of pregnancy 82 pregnant women with a history of recurrent fetal loss and APS Live-birth rates were equivalent between groups (78% vs 76%), mean birth weight was higher in the IVIg group gestational hypertension and diabetes were found significantly more often in the PD group (14% vs 5%), respectively ( p < 0.05) [ 225 ] Case series Patients were treated with heparin (15), LDA (18), and CS (6); additionally, they received IVIg 0.4 g/kg for 5 days monthly from the first or early second trimester 19 pregnancies of 15 women with APS and recurrent fetal loss The live-birth rate was 84%; compared to approximately 70% described in literature without IVIg [ 226 ] Controlled trial In phase III, they received heparin + LDA with or without IVIg 121 women with APS, who failed to achieve live births after 2 IVF attempts with heparin + LDA The birth rate was 41% when IVIg was added and anti-PS or anti-PE involving IgG or IgM isotypes were present, as compared with 17% when H + A alone was administered; the IVF outcome did not improve when IVIg was administered in association with any other single APS antibodies [ 227 ] Controlled trial IVIg 0.3 g/kg every 3 weeks until the 16th to 17th week of pregnancy 38 women after 3 or more consecutive first trimester spontaneous abortions and APS Pregnancy proceeded beyond the first trimester in 34 of the patients (89.4%), and 31 patients (81.4%) gave birth to healthy infants at 37 to 42 weeks' gestation [ 228 ] Case control IVIg 0.5 g/kg for 2 days from the fifth week of pregnancy and repeated every 4 weeks until the 33rd week of gestation 14 women with a history of recurrent spontaneous abortion and APLA No significant biometrical differences between the groups were seen; no fetal or neonatal growth retardation was seen Data were compared to 70 matched uneventful pregnancies Premature rupture of membranes [ 229 ] RCT IVIg (Pentaglobin, Biotest, Frankfurt/Main, Germany) 20 g, 24–48 h after premature rupture of membranes; thereafter, 10 g was administered in weekly intervals 18 women with premature rupture of membranes Infants in treated group showed less laboratory and clinical signs compatible with prenatally acquired infection ( p < 0.002); less chorioamnionitis in treatment group ( p < 0.036) Failure of in vitro fertilization [ 230 ] Meta-analysis IVF along with or without IVIg Women with IVF failure Improvement in live-birth rate ( p = 0.012) [ 231 ] RCT IVIg (Gamimune 5%, Bayer Canada Inc., Etobicoke, Canada) 0.5 g/kg or placebo (saline), first infusion on the day of embryo transfer or during preceding 72 h, second infusion 4 weeks later upon evidence of embryonic heart activity 51 women after IVF failure No significant improvement in implantation, pregnancy, or live birth rate

Perinatal hemochromatosis

Level of evidence B

Although the best level of evidence is not strong, the improvement shown for treated pregnancies is beyond the natural possibility of a subsequent spared pregnancy which has been estimated to be approximately 40% ( Gissen 2004 #110). In view of this data and the difficulty for large RCTs, IVIg may be considered to prevent recurrent perinatal hemochromatosis ( strength of recommendation IIa ).

Recurrent pregnancy loss excluding antiphospholipid syndrome

Level of evidence A

There is evidence that IVIg improves the outcome of pregnancy in secondary recurrent miscarriage (in women that had a previous pregnancy that reached at least the second trimester ( strength of recommendation IIb )). This has so far not been shown for primary recurrent miscarriage ( strength of recommendation III ).

Recurrent pregnancy loss due to antiphospholipid syndrome

Level of evidence A

The evidence is against the use of IVIg in pregnancy of women affected by antiphospholipid syndrome ( strength of recommendation III ).

Prevention of infection after premature rupture of membranes

Level of evidence B

Evidence from a small RCT indicates that IVIg may reduce the rate of fetal infection after premature rupture of membranes ( strength of recommendation IIa ).

Failure of in vitro fertilization

Level of evidence A

The evidence is scarce but the only meta-analysis based on data from three RCTs found a benefit in the number of live births in women treated with IVIg. After in vitro fertilization (IVF) failure, IVIg along with IVF techniques may be weighted ( strength of recommendation IIb ; Table 6 ). Table 6 The use of intravenous immunoglobulins in cardiac disease Disease Ref. Study design Intervention including dose and IVIg preparation used Number of patients Results/response Congestive heart failure (CHF) [ 13 ] RCT Octagam (Octapharma) 0.4 g/kg per day for 5 days followed by monthly dose of 0.4 mg/kg for 5 months, compared with placebo 40 patients with symptomatic CHF (NYHA II/III) and ejection fraction (EF) <40% due to idiopathic dilated cardiomyopathy (42.5%) or secondary to ischemic heart disease; 20 patients (9 idiopathic DCM, 11 coronary artery disease) received IVIg; 20 patients received placebo IVIg induced significant increase of EF by means of 5 EF units, regardless of the cause of CHF, compared to no significant change of EF in the placebo group; improved quality of life in 73% compared to 40% in placebo group; p value < 0.05 Dilated cardiomyopathy (DCM) [ 12 ] RCT Gamimune N, 10% (Bayer Corporation), 1 g/kg IV each day on 2 consecutive days, compared to placebo 62 patients with new-onset DCM and EF ≤40% (with symptoms for less than 6 months); both idiopathic DCM and myocarditis patients were included; 33 patients received IVIg, and 29 patients were treated with placebo Mean EF improved from 0.25 ± 0.08 to 0.41 ± 0.17 following 6 months for all patients; there was no significant difference in EF improvement between IVIg and placebo group Peripartum cardiomyopathy (PPCM) [ 232 ] Retrospective study, case series 2 g/kg of IVIg given as 1 g/kg q.d. on 2 consecutive days along with conventional therapy, compared to conventional therapy alone 17 patients with PPCM; 6 received IVIg; all with NYHA class II–IV and EF < 40%, within 6 months from delivery In the control group, 1 patient died (9.09%), and others had a mean improvement of EF by 13 ± 13 EF units, compared to 26 ± 8 EF units in the IVIg group; p value 0.042 Myocarditis [ 233 ] Case series Total dose of 1 to 2 g/kg IVIg over 48 h (Venilon, Venoglobulin-IH, and Polyglobin-N preparations were used); all patients received conventional therapy 9 patients: 6 patients with acute myocarditis, 3 patients with acute dilated cardiomyopathy; NYHA III and IV Mean EF improved significantly, from 19.0 ± 7.5% to 35.4 ± 9.1% following IVIg treatment; P value < 0.01 [ 234 ] Prospective nonrandomized trial IVIg (Immuno AG, Vienna), total dose of 2 g/kg over a maximum of 24 h; some of the IVIg groups were treated with an additional dose of 1 g/kg a week later, compared with conventional therapy 46 patients with acute onset disease and severely depressed EF; 21 patients received IVIg; a control group of 25 patients was collected from retrospective files There was no significant change of survival in the IVIg group compared to control; IVIg group had a higher fractional shortening than control during 3- to 6-month follow-up period; the control group failed to normalize EF; p value 0.033 Chronic idiopathic pericarditis (CIP) [ 20 ] Case series Five monthly cycles of 0.4 g/kg per day for 5 consecutive days, followed by administration every 2 months 4 patients with CIP Remarkable response in 3 patients, and a long-standing remission with no need for further steroid treatment; 1 patient with partial response Pericardial diseases [ 18 ] Case report Total dose of 2 g/kg of IVIg, and 100 mg/kg per day of acetylsalicylic acid for 14 days 1 patient with Kawasaki disease, left anterior descending artery aneurysm and septated pericardial effusion 2 weeks following treatment initiation, there was disappearance of the pericardial effusion and no change of the coronary aneurysm [ 16 ] Case report IVIg treatment starting at the 16th day following initial presentation, total of 2 g/kg, and 30 mg/kg per day of MP for 5 days 1 patient with Kawasaki disease, complicated by cardiac tamponade Failure of treatment and need for salvage pericardiocentesis [ 19 ] Case series Low-dose IVIg therapy—approximately 0.5 g/kg every 5 ± 2 weeks for 6 ± 6 courses 62 lupus patients, of which several developed pericardial disease 60% of affected patients had resolution of pericardial involvement Kawasaki disease (KD) [ 235 ] Meta-analysis Low (≤80 mg/kg) and high doses (>80 mg/kg) of aspirin and low (≤1 g/kg) to high doses (>1 g/kg) of IVIg over 3–5 days Review of all published papers from 1967 to 1993; 30–60 days of follow-up The rates of coronary aneurysms were significantly reduced due to IVIg therapy compared to aspirin alone; high-dose IVIg had lower aneurysm rates compared with low-dose therapy; higher aspirin dose did not alter outcome; p value < 0.0001 [ 236 ] Meta-analysis of RCT Patients received: (1) various doses of IVIg, plus aspirin, versus placebo; (2) different doses of IVIg (0.1, 0.2, 0.4 g/kg for 5 days); (3) IVIg 0.4 g/kg for 5 days Vs 2 g/kg once; (4) comparison between 4 types of preparations 16 RCTs of patients with KD (1) Significant decrease in new CAAs, fever, and hospitalization at 30 days with IVIg RR (95% CI) = 0.74 (0.61 to 0.90) but only trend at 60 days ( p = 0.06); (2) dose comparisons showed a decrease in the number of new CAAs with increased dose; (3) less CAA for 2 g/kg once RR (95%) = 4.47 (1.55 to 12.86); (4) no difference [ 237 ] Multicenter RCT IVIg 0.4 g/kg for 4 days, with or without aspirin 153 patients (78 with KD, 75 controls) Reduction of echocardiogram-proven CAA from 23% to 8% at 2 weeks ( p = 0.01) and from 18% to 4% at 7 weeks ( p = 0.005) [ 238 ] Case control study IVIg 2 g/kg per day at 1–5 or 5+ days from fever onset 178 patients with KD (89 in each group) Patients treated within 5 days had shorter fever duration ( p < 0.001) and less CAA at 1 year ( p = 0.02) [ 239 ] RCT IVIg 2 g/kg per dose and aspirin; four different brands were used in four groups: Venoglobulin-S (brand A; Alpha Therapeutics, Los Angeles, CA, USA), Gamimune_ N (brand B; Bayer Therapeutics, Elkhart, IN, USA), Intraglobin F (brand C; Biotest Pharma, Dreieich, Germany), “CBSF” human immunoglobulin (brand D; Scottish National Blood Transfusion Service Protein Fractionation Center, Edinburgh, Scotland, UK) 435 patients with KD Patients receiving brand C had higher rates of CAAs ( p = 0.01), nonresponsiveness ( p = 0.001) and giant aneurysm ( p = 0.008) [ 240 ] RCT Patients were divided to 2 groups receiving IVIg 1 or 2 g/kg, plus aspirin 242 children with KD There was no significant difference in the incidence of CAL ( p > 0.05) [ 241 ] Multicenter prospective RCT Group A: Tx with IVIg 2 g/kg and additional 2 g/kg for nonresponders; group B: IVIg 1 g/kg, and additional dose first 1 g/kg then 2 g/kg for nonresponders; IVIg used: Venilon (Teijin Pharma, Japan), Venoglobulin-IH (Venesis, Japan) or Polyglobin-N (Bayer Yakuhin, Japan) 109 patients with KD divided to 2 groups No significant difference in CAA between the patients; discriminate analysis suggested that 52.4% of the patients in group A could be treated with 1 g/kg IVIg only [ 242 ] Multicenter RCT Single infusion of 2 or 0.4 g/kg for 4 days; both received aspirin (100 mg/kg per day through the 14th day of illness, then 3 to 5 mg/kg per day) 549 children with KD Single-dose patients had less fever ( p = 0.001), inflammatory markers, and CAA ( p = 0.004) Rheumatic fever (RF) [ 243 ] RCT IVIg (Intragam, from Common wealth Serum Laboratories) 1 g/kg on days 1 and 2 and 0.4 g/kg on days 14 and 28 59 patients with RF, diagnosed according to Jones criteria; 27 patients received IVIg and 32 patients received placebo IVIg did not affect the natural history of RF during 52 weeks of follow-up Congenital heart block [ 26 ] Case series 1 gm/kg IVIg (Sandoglobulin; Novartis, Bern, Switzerland), at 14th and 18th weeks of gestation; PD (40 mg/day) from the 14th week, which was tapered down to 10 mg/day 8 pregnant women with past history of an affected child with neonatal lupus 1 child was born with erythematosus skin rash, and 1 child had congenital heart block—interestingly, his mother was the only patient that refused PD intake Awaiting for cardiac transplantation [ 244 ] Controlled trial 1 to 3 monthly courses of IVIg 2 g/kg administered in 4 divided daily doses or high-dose IVIg therapy (3 g/kg) in poorly responsive patients; all patients received monthly 0.5–1.0 g/m 2 cyclosporine 16 sensitized patients with left ventricular assist device (LVAD) awaiting cardiac transplantation; results were compared to plasmapheresis ( n = 4) and to cyclosporine alone ( n = 28) Within 1 week of infusion of IVIg, the reactivity of IgG antibodies for allogeneic HLA class I molecules was reduced by a mean of 33%; high-dose IVIg for unresponsive patients resulted in a mean reduction of 20%; IVIg has earlier onset of action and greater efficacy than plasmapheresis; waiting time for donation was significantly reduced from 7.1 to 3.3 months; p value < 0.05 [ 245 ] Retrospective, nonrandomized, controlled trial IVIg, 10 g daily for 3 days or conventional therapy following LVAD transplantation 51 nonsensitized patients with CHF, who received left ventricular assist device transplantation received either IVIg ( n = 26) or conventional therapy ( n = 25) Low-dose IVIg therapy failed to reduce sensitization rate in nonsensitized LVAD patients who received blood transfusion during bridge time to cardiac transplantation [ 246 ] Case series IVIg 2 g/kg given 1 day before the Norwood procedure, repeated 3 weeks and 4 months later 7 infants with hypoplastic left heart syndrome who underwent Norwood procedure with cryopreserved allograft pulmonary artery patch IVIg did not prevent sensitization of the previously unsensitized patients

Congestive heart failure

Level of evidence B

A randomized double-blind study has demonstrated significant increase of ejection fraction (EF) and improved quality of life following IVIg administration, regardless of the congestive heart failure (CHF) cause. CHF is a proinflammatory state due to an increase of cytokines such as TNF-α and interleukin (IL)-1. Some of the cytokines have been shown to induce myocardial dysfunction due to negative inotropic effect [ 11 ]. Another possible mechanism in CHF pathogenesis is mediated by anti-β1 adrenergic receptor ( strength of recommendation IIa ).

Dilated cardiomyopathy

Level of evidence B

Dilated cardiomyopathy (DCM) is caused by various triggers or may be idiopathic. Immune abnormalities and autoantibodies may play a role in the pathogenesis. Nevertheless, no significant effect was noted following IVIg administration in recent-onset DCM compared to placebo [ 12 ]. A trial on 17 patients with idiopathic DCM showed significant improvement of EF and quality of life compared with placebo [ 13 ]. Therefore, IVIg treatment in DCM remains controversial, and it is possible that IVIg treatment is beneficial in specific subpopulation and when treatment is initiated at a certain time window ( strength of recommendation IIb ).

Peripartum cardiomyopathy

Level of evidence C

Peripartum cardiomyopathy (PPCM) is a rare disorder. It is believed that autoimmune mechanisms play a role in the pathogenesis. In a small nonrandomized retrospective trial, there was a significant improvement of EF following IVIg administration compared with conventional treatment. Although there is partial evidence of IVIg effectiveness in PPCM, its use should be considered due to the generally poor prognosis of PPCM patients who show no clinical improvement ( strength of recommendation IIa ).

Myocarditis

Level of evidence B

Treatment with CS or cytotoxic agents was found ineffective [ 14 , 15 ]. In an RCT trial of 62 patients with new-onset DCM of which some had myocarditis [ 12 ], there was no significant difference in EF improvement between IVIg and placebo group. Nevertheless, in a prospective nonrandomized trial, there was a significant improvement of fractional shortening compared to control. We conclude that further research is warranted regarding IVIg use in myocarditis due to inconclusive results ( strength of recommendation IIb ).

Pericardial diseases

Level of evidence C

Pericardial involvement in Kawasaki disease may be seen in 6.3% to 24.5% of patients and may be complicated by cardiac tamponade despite IVIg therapy [ 16 , 17 ], occasionally due to rupture of coronary aneurysms. There is a consensus that IVIg significantly decreases coronary aneurysms, but little is known regarding direct effect on the pericardium in the setting of mucocutaneous lymph node disease. It seems that septated pericarditis in Kawasaki disease response dramatically to IVIg but further research is warranted [ 18 ] ( strength of recommendation IIb ).

Low-dose IVIg therapy was found to be beneficial in 60% of lupus patients with pericarditis in a case series [ 19 ] ( strength of recommendation IIa ).

Chronic idiopathic pericarditis (CIP) appears in up to 25% of acute pericarditis cases. It may be associated with viral infections and autoantibodies [ 20 ]. There is limited evidence on the role of IVIg as an alternative therapy for prolonged steroid or colchicine treatment in CIP ( strength of recommendation IIa ).

Atherosclerosis

Atherosclerosis is believed to be mediated also by humeral and cellular immune mechanisms. There are accumulating data that support a role of IVIg in prevention of atherosclerosis. Possible mechanisms include decrease of matrix metalloproteinase 9 secretion from mononuclear cells [ 21 ], increase of IL-10 [ 11 ], and decrease of oxidized low-density lipoprotein uptake by macrophages [ 22 ]. Nevertheless, clinical trials are required in order to establish the relationship between IVIg use and atherosclerosis therapy.

Kawasaki disease

Level of evidence A

It is the leading cause of acquired heart disease in the USA. Kawasaki disease is an FDA-approved absolute indication for IVIg therapy. The frequency of CA aneurysm development and associated morbidity and mortality have been dramatically decreased as a result of IVIg therapy when given within 10 days following the onset of fever. A single dose of 2 g/kg of IVIg over 10 H is usually recommended along with a high dosage of aspirin [ 23 ]. Failure of IVIg treatment in Kawasaki disease and the need for several consecutive IVIg doses is usually caused by delayed initiation of treatment [ 16 ]. Detailed treatment algorithms may be found elsewhere [ 24 ] ( strength of recommendation I ).

Rheumatic fever

Level of evidence B

Because there is no efficient treatment for established rheumatic carditis, several agents has been proposed in an attempt to change the natural history. IVIg has failed to change clinical outcome and disease progression and therefore is not recommended for treatment of acute rheumatic fever ( strength of recommendation III ).

Congenital heart block in neonatal lupus erythematosus

Level of evidence C

NLE is a rare disease that is associated with anti-Ro and anti-La autoantibodies [ 25 ]. A single case series of eight subjects had nonconclusive results regarding the effect of IVIg and PD in prevention of congenital heart block [ 26 ] ( strength of recommendation IIb ).

Cardiac transplantation

Level of evidence C

IVIg has anti-idiotypic properties, as well as human leukocyte antigen molecules that may neutralize high panel reactive antibodies in sensitized patients awaiting cardiac transplantation. There is some evidence for IVIg benefit in patients with left ventricular assist device who are awaiting cardiac transplantation (strength of recommendation IIa). Nevertheless, IVIg did not reduce sensitization in previously unsensitized patients who underwent Norwood procedure ( strength of recommendation III ; Table 7 ). Table 7 The use of intravenous immunoglobulins in ophthalmic disease Disease Ref. Study design Intervention including dose and IVIg preparation used Number of patients Results/response Ophthalmic IgA bullous disease [ 247 ] Case report Monthly IVIg treatment, 4 g/kg per month, with graduate discontinuation following clinical improvement 1 patient with chronic cicatrizing conjunctivitis due to linear IgA bullous disease with poor response to topical or systemic CS Improvement of clinical symptoms with maximal effect 10–12 days following infusion; decrease of circulating IgA anti-97-kDa epidermal protein Mucous membrane pemphigoid (MMP) [ 27 ] Nonrandomized controlled trial IVIg, 2 g/kg per cycle, cycles were repeated every 2–4 weeks, compared to conventional immunosuppressive therapy 16 patients that were equally divided to control and IVIg group Remission was achieved after 4 months in IVIg group vs 8.5 months in control group; IVIg had less recurrence and decreased progression; p value < 0.05 Ocular Behcet's disease [ 90 ] Case series IVIg 0.4 g/kg per day: 5 times in first week, 3 more in the next months and once every 20 days for total of 3 months 4 patients refractory to CS and cyclosporine A Control of acute inflammation and preservation of remission for 1 year; marked improvement of visual acuity Optic neuritis [ 248 ] RCT 27 patients were treated with IVIg (Gamimune N; Bayer Pharmaceutical Division, West Haven, CT, USA) 0.4 g/kg per day for 5 days followed by 3 monthly single cycles vs placebo ( n = 28) 55 patients with multiple sclerosis and visual loss due to optic neuritis No difference between treatment groups was observed; there was no absolute reversal of persistent visual loss; the trial was terminated by the National Eye Institute [ 249 ] RCT IVIg 0.4 g/kg per day (Immunoglobulin SSI liquid; Statens Serum Institute, Copenhagen, Denmark), infused on days 0–2, and 1 to 2 months later ( n = 34) vs placebo ( n = 34) 68 patients with recent visual accuracy loss; 34 patients received IVIg (of which 15 had multiple sclerosis), compared with 34 patients who received placebo (of which 8 patients had multiple sclerosis) No immediate or delayed effects were observed; there was no change in visual acuity; MRI findings and visual evoked potential results Inflammatory pseudotumor of orbit [ 250 ] Case report IVIg 2 g/kg divided over 4 days 1 patient with inflammatory pseudotumor of the orbit, resistant to systemic CS, and radiation therapy Both clinical and radiographic improvement within days Birdshot retinochoroiditis [ 251 ] Case series IVIg 0.4 g/kg per day for 4 days; then 0.6 g/kg per day for 2 days, every 4 weeks 37, of which 18 were followed up Visual acuity of 53% of patients' eyes has increased by 2.6 ± 1.5; in 29% of patients, visual acuity remained stable, and in 18% of eyes VA have decrease [ 29 ] Case series IVIg 1.6 g/kg every month for 6 months, followed by 1.2–1.6 g/kg every 6–8 weeks 18 patients In patients with visual acuity of 20/30, there was increase in visual acuity in 53.8% of eyes and decrease of acuity in 7.7% while there was no change in the remaining eyes Orbital myositis [ 252 ] Case report IVIg (Venimmun) 0.3 g/kg per day for 3 days 1 patient intolerant to CS treatment and poor clinical response Both clinical and tomographic resolution within 2 weeks Refractory uveitis [ 253 ] Case series IVIg (Baxter Healthcare, Glendale, CA, USA), 0.5 g/kg per day for 3 days each month; median of 7.5 cycles 10 patients with poor response to immunosuppression (some cases were idiopathic, others were secondary to sarcoidosis, Behcet, inflammatory bowel disease, and birdshot retinochoroiditis) 50% sustained improvement of visual acuity, 20% have required a reduced doses of immunosuppressive therapy without disease progression; the patient with sarcoidosis had improved vision and reduced need for immunosuppression, although that effect was not sustained 4.5 months following treatment discontinuation; the Behcet patient showed marked improvement [ 254 ] Case series IVIg, 1–2.5 g/kg per cycle over 3 days; cycles were repeated every 2–4 weeks initially and every 5 to 6 weeks after effect was observed; treatment time averaged at 16.8 months 5 patients unresponsive to conventional therapy, of which 1 patient had juvenile idiopathic arthritis and 1 patient had psoriatic arthritis; 1 patient had retinal vasculitis and APLA; the other 2 cases were idiopathic In 60% (2 idiopathic cases, 1 patient with vasculitis and APLA), treatment was effective in controlling inflammation, and visual acuity remained stable or improved Graves' ophthalmopathy [ 255 ] Prospective nonrandomized 35 patients were treated with IVIg and 27 with CS 62 patients with Graves' ophthalmopathy 76% response in IVIg-treated patients compared to 66% in CS group, in a manner that was statistically insignificant; side effects were more common in patients receiving CS therapy [ 256 ] RCT 21 patients were treated with 6 cycles of 1 g/kg IVIg for 2 days every 3 weeks; 19 patients were treated with oral prednisolone (starting dose 100 mg/day) 40 patients No marked difference between IVIg (62% response) and prednisolone (63% response); both groups had significantly improved proptosis, visual acuity, decrease of intraocular pressure, and decrease of eye muscle area Paraneoplastic visual loss [ 257 ] Case series 2 patients were treated with IVIg 0.4 mg/kg per day for 5 days; 1 patient received single-dose d/t treatment intolerance 3 patients 1st patient improved from distinguishing hand movement to 20/40 and 20/50 OS; improved visual fields 2nd patient, no improvement 3rd patient, improved visual field without change in visual acuity [ 258 ] Case report IVIg, as well as radiotherapy and surgical resection 1 patient with melanoma-associated retinopathy Improvement in visual fields over 1 year of follow-up

Ophthalmic IgA bullous disease

Level of evidence C

Linear IgA bullous disease may affect the eye (in 67% of patients) and may present as chronic cicatrizing conjunctivitis. Systemic disease may be treated with systemic CS and dapsone. In poorly responsive patients, IVIg treatment may be used, although its use should be further investigated ( strength of recommendation IIa ).

Mucous membrane pemphigoid

Level of evidence C

Mucous membrane pemphigoid (MMP) may involve the eye. There is some evidence for the beneficial effect of IVIg in MMP that involves the eye. IVIg may provide more rapid control of symptoms and prevents remissions during long-term follow-up [ 27 , 28 ]. This notion should be supported by larger randomized trials ( strength of recommendation IIa ).

Ocular Behcet’s disease

Level of evidence C

There are some but limited data regarding the potential benefit of IVIg use in Behcet's disease. Further study is required. Nevertheless, IVIg should be carefully considered in patients resistant to conventional immunosuppressive therapy ( strength of recommendation IIa ).

Optic neuritis

Level of evidence A

The natural history of optic neuritis in multiple sclerosis patients is not altered by IVIg transfusion, neither clinically nor radiologically. Therefore, IVIg is not recommended in that setting ( strength of recommendation III ).

Inflammatory pseudotumor of orbit

Level of evidence C

There is anecdotal evidence for the possible beneficial role of IVIg in the treatment of inflammatory pseudotumor of orbit ( strength of recommendation IIb ).

Birdshot retinochoroiditis

Level of evidence C

Birdshot retinochoroiditis is a rare inflammatory disease (bilateral autoimmune posterior uveitis of idiopathic origin). Without immunosuppressive treatment, a progressive visual deterioration will occurs in 80% of patients [ 29 ]. There is supporting evidence for the use of IVIg, especially in patients unresponsive to other therapies ( strength of recommendation IIa ).

Orbital myositis

Level of evidence C

It is caused by inflammatory process of unknown etiology, which is confined to the orbit. There are very limited data on the effect of IVIg in patients with orbital myositis. Such treatment might be considered in symptomatic patients, resistant to other therapies ( strength of recommendation IIa ).

Refractory uveitis

Level of evidence C

Most cases of refractory uveitis (RU) are associated with autoimmune mechanisms. There are some data supporting the use of IVIg in resistant RU, although more research is required in order to establish clinical guidelines (strength of recommendation IIa).

Graves' ophthalmopathy

Level of evidence B

It seems that IVIg is as efficient as CS in the treatment of Graves' ophthalmopathy. Nevertheless, despite similar clinical response to treatment, IVIg was associated with fewer side effects and the study group showed more tolerance towards it. Therefore, we conclude that IVIg should be considered in CS intolerance ( strength of recommendation I ).

Paraneoplastic visual loss

Level of evidence C

There is limited evidence for the benefit of IVIg in cancer-associated retinopathy. Nevertheless, since spontaneous recovery usually does not occur, IVIg may be used in progressive visual compromise in addition to CS or plasmapheresis ( strength of recommendation IIb ; Table 8 ). Table 8 The use of intravenous immunoglobulins in kidney diseases Disease Ref. Study design Intervention including dose and IVIg preparation used Number of patients Results/response Membranous nephropathy [ 259 ] Retrospective uncontrolled trial IVIg 0.4 g/kg every 21 days (mean duration of treatment was 15 months equal to 21 cycles) 13 adult patients (8 males, 5 females) with primary membranous glomerulonephritis 5 patients had complete remission 5 patients had partial remission 3 patients no clinical remission but presented marked reduction in proteinuria [ 260 ] Case series IVIg 0.4 g/kg per day for 3 days every 21 days (3 courses), then once every 3 weeks for 10 months 9 patients with biopsy-confirmed idiopathic membranous nephropathy 5 patients with normal renal function: 4 had complete remission, 1 had partial remission 4 patients with moderate renal insufficiency: 1 had complete remission, 2 had partial remission, 1 had no response [ 261 ] Retrospective analysis IVIg 0.1–0.15 g/kg per day for 6 days, 1–3 courses 86 with primary membranous glomerulonephritis 30 patients were treated with IVIg: 13 patients had complete remission; 11 patients had partial remission; 3 patients had continued nephrotic state with renal dysfunction; 3 patients reached end-stage renal disease IgA nephropathy [ 262 ] Single-arm, nonrandomized study IVIg 2 g/kg monthly for 6 months 14 patients with progressive IgA nephropathy 6 patients received IVIg; the mean loss of renal function and proteinuria were significantly reduced in the IVIg group ( p = 0.024, p = 0.015, respectively) [ 62 ] Open prospective cohort study IVIg 2 g/kg per month for 3 months followed by IMIg for another 6 months 11 patients with moderate IgA nephropathy Proteinuria, glomerular filtration rate, and histologic index of activity were significantly decreased BK-virus-associated nephropathy in renal allograft recipients [ 263 ] Case series IVIg 2 g/kg over 2–5 days + immunosuppression 8 renal allograft recipients with BK-virus-associated nephropathy 88% of the patients were dialysis free and had stable renal function after follow-up of 15 months [ 264 ] Case report IVIg 0.6 g/kg, 5 doses repeated every 4–6 weeks A pediatric renal transplant patient recipients with BK-virus-associated nephropathy Stabilized renal function, reduced viral load, and resolved histological findings were noted after IVIg treatment ANCA-associated rapidly progressive glomerulonephritis (RPGN) [ 265 ] Case series IVIg 0.4 g/kg per day for 5 days + CS ± CP after IVIg Twelve patients with MPO-ANCA-associated RPGN (7 men, 5 women) After IVIg treatment, a significant reduction was noted in white blood cell count ( p < 0.05), in C-reactive protein values ( p < 0.001), in Birmingham vasculitis; Activity Score ( p < 0.001) and in the rate of change in 1/Cre ( p < 0.05) [ 57 ] Case series IVIg 0.4 g/kg per day for 5 days + immunosuppressive therapy 30 patients with MPO-ANCA-associated RPGN (male 17, female 13) After IVIg, significant reduction in CRP ( p < 0.001), improvement in serum creatinine in 63% of patients; at 3 months, disease activity was completely reduced; at 6 months, renal survival rate was 92% and life survival was 93% [ 266 ] Case report IVIg (Omr-IgG-am5%IV) 0.5 g/kg per day for 4 days after immunosuppressive therapy A 68 year-old woman with RPGN Significant improvement in renal function after IVIg treatment [ 267 ] Case reports IVIg A 66-year-old male and a 14-year-old boy with MPO-ANCA-associated RPGN Significant improvement in both patients including renal function after IVIg treatment Renal transplant rejection [ 268 ] Prospective pilot trial IVIg 1 g/kg per dose every week for 4 weeks + rituximab 1 week after last IVIg infusion 6 pediatric renal transplant recipients with chronic antibody-mediated rejection 4/6 responded to IVIg with significant improvement in glomerular filtration rate ( p < 0.05); 2/6 no response [ 269 ] Case report IVIg 0.5 g/kg every other day for 4 cycles + rituximab + plasmapheresis A 46-year-old female renal transplant recipient with antibody-mediated rejection Improvement in renal function [ 270 ] Case report IVIg 0.15 g/kg within 72 h of transplantation, and 0.1 g/kg every 2 weeks for 4 doses, followed by monthly infusions for 2 doses + plasmapheresis + monoclonal anti-T lymphocyte antibody therapy A 14-year-old renal transplant recipient with antibody-mediated rejection Improvement in renal function and reverse of Ab-mediated rejection [ 271 ] Case series IVIg 2 g/kg 7 renal transplant recipient with antibody-mediated rejection IVIg-induced reversion of acute rejection in all patients and reduced donor-specific anti-HLA alloantibody levels Lupus nephritis [ 272 ] RCT During 18 months, 5 received IVIg 0.4 g/kg once a month, 9 continued CP 14 patients with proliferative lupus nephritis Treatment with IVIg as maintenance therapy was safe and effective as CP [ 273 ] Case series IVIg, 0.4 g/kg for 5 days, of ISIVEN (Istituto Sierovaccinogeno Italiano I.S.I.S.p.A, Italy). 7 lupus nephritis patients who failed to respond to at least PD and CP All patients had a beneficial response to IVIg; all had significant decrease in proteinuria [ 274 ] Case report IVIg 2.8 g/kg, one dose A 39 year-old female SLE patient with lupus serositis and nephritis Clinical improvement and significant decrease in proteinuria. [ 275 ] Case report IVIg 12.5 g/day for 5 successive days after CS and plasmapheresis treatment A 34-year-old Japanese female patient with rapidly progressive lupus nephritis associated with anti-MPO antibodies Significant improvement of renal function after IVIg treatment

Lupus nephritis

Level of evidence B

A few case reports and a single RCT clearly indicate the efficacy of IVIg in the treatment of lupus nephritis. In all cases, patients had a beneficial response to IVIg and a significant improvement of renal function was noted. Therefore, IVIg is recommended as an alternative treatment in lupus nephritis or in cases that conventional immunosuppressive treatment fails ( strength of recommendation I ).

Renal transplant rejection

Level of evidence C

Although evidence for the use of IVIg in renal transplant rejection is limited to case reports and case series results showed that IVIg may be effective for treating acute or chronic renal transplant rejection. IVIg may improve renal function and reverse Ab-mediated rejection. IVIg may be considered among the treatment options generally together with immunosuppressive therapy ( strength of recommendation I ).

ANCA-associated rapidly progressive glomerulonephritis (RPGN)

Level of evidence C

There is weak evidence indicating significant benefit from the use of IVIg in antineutrophil cytoplasmic antibody (ANCA)-associated RPGN. Several case series and case reports showed that IVIg may improve renal function and therefore is recommended as a potential therapy for ANCA-associated RPGN ( strength of recommendation I ).

BK-virus-associated nephropathy in renal allograft recipients

Level of evidence C

The use of IVIg in BK-virus-associated nephropathy in renal allograft recipient is limited only in a few case reports. Nevertheless, in these cases, IVIg showed significant efficacy and with concomitant reduction of immunosuppression it may be considered as one of the treatment options in this disease ( strength of recommendation I ).

IgA nephropathy

Level of evidence B

Results coming from a single-arm nonrandomized study and a prospective cohort study showed that IVIg may be effective in treating severe IgA nephropathy and therefore it may be considered as a possible treatment option. However, RCTs are needed to confirm this efficacy ( strength of recommendation I ).

Membranous nephropathy

The efficacy of IVIg in membranous nephropathy was studied in few retrospective trials and a case series. Results from these studies indicate that IVIg may be effective in induction of remission. Although there is no strong evidence, IVIg may be considered as an additional option in treatment of membranous nephropathy (strength of level of evidence C; recommendation I ; Table 9 ). Table 9 The use of intravenous immunoglobulins in dermatologic diseases Results/response Number of patients Intervention including dose and IVIg preparation used Study design Ref. Disease 21/21 reached sustained remission; mean time to clinical response 4.5 months; maintenance therapy for a mean 22.7 months; compared to pretreatment period the study subjects received a lower dosage of CS and immune-suppressive therapy, had fewer side effects, recurrences, and relapses, needed fewer hospital admissions and days of hospital stay ( p < 0.001), and reported better quality of life ( p < 0.0001) 21 patients with severe pemphigus vulgaris unresponsive to corticosteroid and immune-suppressive agents Monotherapy 2 g/kg given in 3 days in 4-week interval until complete healing, afterwards after 6, 8, 10, 12, 14, and 16 weeks if patient is disease free; end point—disease free with a 16-week interval between the 2 infusion cycles; adjunctive to other systemic therapy, not effective in the beginning of trial Uncontrolled trial [ 276 ] Pemphigus vulgaris 10/12 (83%) responded, 6/12 (50%) had complete remission and 4/12 (33%) partial response; 72% decline of pemphigus antibody levels and steroid-sparing effect 12 patients with severe unresponsive pemphigus vulgaris IVIg for 6 months as adjuvant to immune-modulating therapy Uncontrolled trial [ 277 ] No new lesions and 72% decline of pemphigus antibodies levels after 1 week, 80% reduction of extent of existing lesions in 5/6 patients after 2 weeks, 41% reduction of steroid doses after 3 weeks 6 patients with active pemphigus vulgaris, unresponsive to at least 2 months of CS therapy IVIg 2 g/kg in 5-day cycles (as 5% solution, Venoglobulin S; Alpha Therapeutics Co, LA, CA, USA) concurrent with CS and cyclophosphamide 100–150 mg/day Uncontrolled trial [ 278 ] Significant reduction of total PD dose ( p = 0.004), duration of PD therapy ( p = 0.003), and number of relapses ( p < 0.001); CS was discontinued over a mean period of 4.3 months 15 patients with steroid-dependent pemphigus vulgaris, mean follow-up of 6.2 years IVIg 1 to 2 g/kg given in 3 doses on 3 consecutive days as a 4- to 5-h infusion at a frequency of every 3 to 4 weeks adjunctive to CS (no other immunosuppressive therapy was allowed); intervals were increased to 6, 8, 10, 12, 14, and 16 weeks, if clinical response was achieved Retrospective analysis [ 279 ] 38/39 on adjunctive therapy improved; in monotherapy group, no change in 2 patients, worth in 1 42 patients with pemphigus vulgaris IVIg 2 g/kg per month in 37 patients; 0.3 g/kg per day in 4 patients, 0.25 g/kg per day in 1 patient; Sandoglobulin® in 10, Puimmun® in1, NA in 31 adjunctive in 39, monotherapy in 3 Review of published case reports [ 238 ] 6/7 did not respond; 1/7 had partial response with >50% improvement (but died 1 month after IVIg cycle of pneumonitis) 7 patients with pemphigus vulgaris As adjunctive therapy in the dose of 2 g/kg per cycle, 4/7 patients received Venoglobulin®; other 3 patients received Gammagard/Gammar P.I.V/Gamimune; mean duration of treatment was 7 months Case series [ 280 ] 11/11 had effective clinical response in mean of 5.3 months, clinical remission for a mean period of 18.6 months after discontinuation of IVIg; After IVIg, the study subjects received a lower dosage of CS ( p = 0.001), had fewer side effects ( p = 0.002), recurrences, and relapses ( p = 0.001), had fewer hospital admissions and days of hospital stay ( p < 0.01), and had better quality of life ( p = 0.001) compared to pretreatment period 11 patients with refractory pemphigus foliaceus IVIg 2 g/kg given over 3 days in 4-week interval until complete healing, afterwards after 6, 8, 10, 12, 14, and 16 weeks if patient is disease free; end point—disease free with a 16-week interval between the 2 infusion cycles; adjunctive to other systemic therapy, previously not effective Uncontrolled trial [ 281 ] Pemphigus foliaceus 8/8 significant reduction of antidesmoglein antibodies after 4 months of treatment ( p NA), nondetectable titers after 13 months, serological remission after additional observation period of 5 months 8 patients with severe pemphigus foliaceus IVIg Uncontrolled trial [ 282 ] CS gradually discontinued over a mean period of 2.8 mo, with resulting reduction of PD total dose ( p = 0.005), total duration of PD treatment ( p = 0.02) and number of relapses ( p = 0.002) according to pre-IVIg therapy. 7 steroid dependent pemphigus foliaceus patients. In the beginning of the trial adjunctive to CS and as monotherapy afterwards. Uncontrolled trial [ 283 ] All improved 28 patients with pemphigus foliaceus Adjunctive IVIg 1 to 2 g/kg per month, 0.27 g/kg per month in 1, continued for several weeks to more than 5 months Review of published case reports [ 238 ] 15/15 clinical response within mean of 2.9 months; all patients demonstrated fewer hospital admissions, fewer relapses and recurrences, significant steroid-sparing effect (were tapered over a mean period of 3.3 months), and quality of life improvement compared to pre-IVIg therapy ( p < 0.0001) 15 patients with recurrent bullous pemphigoid despite oral PD and systemic immune-modulating treatment IVIg 2 g/kg over 3 days by 4–5-h infusion adjunctive to oral PD, given every 4 weeks, until clinical stabilization; intervals were gradually increased to 6, 8, 10, 12, 14, and 16 weeks (mean number of cycles 14.7) Uncontrolled trial [ 284 ] Bullous pemphigoid 12/17 (70%) improved; 5/17 (30%) had no change; in some patients, high-dose IVIg had systemic steroid-sparing effect; the lack of response was observed in low-dose or single-effusion cases; early treatment, multiple treatment cycles, and concomitant immunosuppressive treatment led to longer and more sustained remissions 17 patients with severe bullous pemphigoid 15 patients received high-dose IVIg 2 g/kg per month for 1 month (12 patients) to 3 months (1 patient); 2 patients received 0.1 and 0.3 g/kg per day for 5 days (low dose), 10 patients as monotherapy and 8 adjunctive to immunosuppressive therapy Review of published case reports [ 285 ] 1/3 complete response after 4 cycles, maintained with 5 additional cycles; 2 patients had no response 3 patients with bullous pemphigoid Adjunctive therapy with 2 g/kg per month of Venoglobulin® in 2 and Carimune® in 1 of 3 patients for mean 7 months Case report [ 280 ] 19/22 improved on adjunctive therapy, 8/12 improved on monotherapy within 2 weeks–4 months 34 patients with bullous pemphigoid Adjunctive 22, monotherapy in 12 2 g/kg per month in 32 patients, 0.1 g/kg per day for 5 days and 0.3 g/kg per day for 5 days in 2 patients; Venoglobulin® in 11, Sandoglobulin® in 4, NA in 23 continued up to 14 months Review of published case reports [ 238 ] Clinical response in 7/7 patients, treated with IVIg, after a mean period of 4.5 months, sustained remission after a mean treatment period of 26.9 months, improvement of quality of life after IVIg therapy ( p < 0.001); reduction of antibody titers in both groups ( p = 0.015), but faster in IVIg group ( p = 0.03) 7 patients (mean age of onset 55.5) on IVIg monotherapy vs. 7 random patients (mean age of onset 55) with severe (+3) oral pemphigoid; treatment period 12 months Monotherapy with 1 to 2 g/kg per month IVIg vs. conventional immunosuppressive treatment (PD and dapsone or AZA or MTX or tacrolimus or CP); adjunctive local treatment with sublesional injections of triamcinolone acetonide (proven not to be systemically absorbed by serum cortisol levels) was given to patients in both groups Controlled trial [ 286 ] Mucous membrane pemphigoid Significant improvement, reduction of relapses, duration and total dosage of corticosteroid therapy and quality of life after IVIg ( p NA) 15 patients with severe mucous membrane pemphigoid IVIg 1 to 2 g/kg per month Uncontrolled trial [ 283 ] All patients improved within 2–6 months on combination therapy and within 4–6 months on monotherapy, steroid-sparing effect in adjunctive therapy group 43 patients with mucous membrane pemphigoid IVIg 1–3 g/kg over 3–5 days for 2–4-weeks; adjunctive/monotherapy 28/15. Review of published case reports [ 238 ] Improved 3/3 on adjunctive and 2/3 monotherapy, 1/1 UV protection 7 patients with epidermolysis bullosa acquisita 16–59 years old, all males IVIg 0.4 g/kg per day for 5 days, 2–6 weeks (4), 2 g/kg per day 2 weeks (1), 0.04 g/kg per day for 5 days 3–4 weeks (1), 1.2 g/kg per month (1) Polyglobulin® in 1, Sandoglobulin® in 3, NA 3; adjunctive therapy 3, monotherapy 3, 1 UV protection for 1–4 months Review of published case reports [ 238 ] Epidermolysis bullosa acquisita All improved 3 patients 45–67 years old with linear IgA disease Sandoglobulin® 0.4 g/kg per day over 5 days in 1 patient; 2 patients received 4 g/kg per month regiment (preparation NA); 2 patients received CS as additional treatment Review of published case reports [ 238 ] Linear IgA disease Complete response after 5 cycles of IVIg (3.5 months), IVIg continued for additional 10.5 months 1-week-old newborn with linear IgA disease Adjunctive therapy with Venoglobulin® 1 g/kg every 2–4 weeks for 14 months Case report [ 280 ] Steroid-sparing effect, maintained with cyclosporine and low-dose prednisolone; cyclosporine was stopped 16 months after delivery 17-year-old female with pemphigoid gestationis, developed at 20 weeks gestation in her 1st pregnancy 2 g/kg per month for 2 months adjunctive to CS Case report [ 287 ] Pemphigoid gestationis Objective response in all patients within a mean of 2 days, skin healing within 8.3 days, slow healing in patients with underlying diseases, an overall survival rate of 100% 12 patients with SJS (mean age 44) Commercially available IVIg at a mean dose of 0.6 g/kg per day for an average of 4 days as monotherapy Retrospective multicenter study [ 288 ] Stevens–Johnson syndrome The average duration of fever was 8 days in IVIg-treated vs. 14 in non-IVIg-treated group ( p = 0.06); the mean stay in hospital was 12 days in IVIg-treated vs.15 days in non-IVIg-treated group ( p = 0.5) Total of 12 patients (mean age 6 years), 7 IVIg-treated and 5 non-IVIg-treated IVIg as single infusion at 1.5–2.0 g/kg given on an average of 3 hospital days Retrospective series report [ 289 ] No mortality, arrest of disease progression in 1–5 days (mean 2.83), re-epithelialization in a mean of 7.33 days (range 5–13); the average duration of hospital stay was 12.5 days 12 patients (average age 27.2 years, 4 children 7–12 years old); the average affected body area was 57.5% IVIg 0.5–1.0 g/kg per day for 4–5 days adjunctive to standard care protocol, infusion started on average 1.58 days Uncontrolled trial [ 290 ] Toxic epidermal necrolysis 90% of patients survived; one patient with previous history of severe heart disease died as a result of cardiac arrest during the first day of treatment 10 patients with TEN with predicted mortality rate 35% according to SCORTEN IVIg 0.4 g/kg per day for 5 days started within 3 days from the onset of TEN Prospective single center uncontrolled [ 291 ] Progression of epidermal detachment in 22/34, more deaths than predicted by prognostic SCORTEN score (11 (32%) instead of 8.2 (24%)), most deaths in elderly with renal impairment 34 patients with a mean of 4.3 days after onset of SJS ( n = 9), SJS/TEN ( n = 5), TEN ( n = 20) IVIg 2 g/kg within 2–5 days (30 patients treated with Tegeline (Laboratoire francais du Fractionnement et des Biotechnologies, France), 2 with Sandoglobulin® (Novartis, France), 2 with Gammagard ® (Baxter, France), only Gammagard did not include sucrose) Uncontrolled trial [ 292 ] Mortality rate was 20% in IVIg-treated patients vs. 50% in non-IVIg group (overall mortality of 33%) 9 patients with TEN—all treated with CS; 5/9 received IVIg as adjunctive therapy IVIg 0.75–1 g/kg per day for 3 days adjunctive to intravenous prednisolone 0.25–0.5 g/day for 1–3 days Retrospective series report [ 293 ] All survived 3 patients with 30–70% epidermal detachment IVIg 0.5 g/kg per day for 4 days (2 patients), 1 patient was switched after 24 h to 0.6 g/kg per day for 2 days due to further deterioration Case series [ 294 ] 7/7 survived, a cessation of blistering in 7/7 patients within an average of 2 days; in published cases, time to objective response could be ascertained in 20 patients: cessation of blistering after an average of 2.5 days; patients with concomitant CS treatment were noted to have a longer time to objective response 7 pediatric patients with SJS and 28 published pediatric cases of SJS (12), SJS/TEN (5), and TEN (11) treated with IVIg 7 patients IVIg (Gamimune) in an average dose of 2 g/kg over 4 days (on days 1, 2, 4, and 6) initiated an average of 2.7 days after onset, in 5 cases adjunctive to CS in 28 published cases, an average total dose of 2.5 g/kg initiated 3.75 days after blister onset Retrospective case series and review of published case reports [ 295 ] Time to objective response was 2.3 ± 1.2 days; duration of IVIg treatment was 4 ± 0.9 days; objective response rate was 90%; survival rate was 88%; time to complete healing was 15 ± 9.5 days; the odds of survival decreased per year of life ( p = 0.02) and increasing epidermal detachment ( p = 0.03); more underlying disease in the group of nonsurvivors ( p = 0.03) 48 patients with TEN (mean age 44), with skin detachment in 44.8 ± 22.5% and mucous membrane involvement in 91.7% of cases Commercially available IVIg at mean dose of 0.7 g/kg per day for a mean of 4 days given as monotherapy 7.3 ± 6 days from onset of TEN Retrospective multicenter [ 296 ] 83% reduction of mortality (1 patient died instead of 5.8 expected based on SCORTEN) 16 patients with TEN IVIg for 4 days (15 patients 1 g/kg per day and 1 patient 0.4 g/kg per day); 2 patients received IVIg without sucrose Retrospective series report [ 297 ] The average time to arrest of progression was 2.1 days; complete re-epithelialization was 8.1 days and length of hospitalization 13.6 days; no mortality 8 pediatric patients with TEN with mean surface involvement of 67% Monotherapy of IVIg 0.5–0.75 g/kg per day for 4 consecutive days, started with average delay of 3.2 days after blisters onset Retrospective series report [ 298 ] No difference in length of stay, mechanical ventilation, severity of inflammatory response or incidence of sepsis, wound progression, time to healing, and mortality 16 TEN patients with initial rash involving 65 ± 29%, treated with IVIg vs. 16 patients with TEN initial rash involving 65 ± 27% not treated with IVIg IVIg (Gamimune® N, Bayer Inc., Toronto, CA) 0.2 to 0.7 g/kg per day according to discretion of attending physician on duty, as 5% or 10% solution according to availability, for 4 ± 1 day Retrospective [ 299 ] No difference of SCORAD index and in global evaluation of disease severity by patients at day 30 10 adult patients (mean age 28) with sever atopic dermatitis IVIg 1 g/kg per day (Sandoglobulin®, Sandoz, France) immediate or delayed by 1 month (meanwhile intensive therapy with emollients and topical CS (limited to class II 60 g/month)), for 2 days in 8-h infusion, as monotherapy RC evaluator-blinded trial [ 300 ] Atopic dermatitis Improvement in skin score (mEASI) was apparent in responders (4/6 patients) from 2 to 3 months and continued to improve over a 6-month period; after 7 months, there was a significant reduction of the overall mEASI; CD69-expressing T cells decreased to 60% from baseline; no change of TNF-a and IFN-g 6 adult patients with severe stable atopic dermatitis Flebogamma® 5% 2 g/kg per month given in 2–5 days for 6 months as adjunctive treatment, followed for 3 months Open, single center, prospective [ 301 ] 3/3 patients improved skin scores, allowing reduction of steroid dose 3 adult patients with severe atopic dermatitis and steroid-related side effects Alphaglobin® (Grifols, UK) or Sandoglobulin ® (Novartis, UK) 2 g/kg per month in 3–5 days adjunctive to CS Aza, Hxc Case report [ 302 ] 9/10 were available for analysis: 6/9 showed slight improvement of skin lesions; 2/9 were unchanged and 1/9 worsened; there were no steroid-sparing effect, change in mean IgE, lymphocyte response to PHA, Candida, tetanus, and anti-CD3 antibody, and change in RAST positivity to negativity 10 patients (7–64 years old): 1 patient with hyper-IgE syndrome and 9 patients with atopic dermatitis Adjunctive to CS in 6/10 Venoglobulin® I (10%) 2 g/kg per month for 7 months Open, single center [ 303 , 304 ] 9/10 patients less than 6 years old improved on monotherapy; 1 patient with WAS failed to improve after 1 treatment cycle; 17/22 adults received adjunctive therapy; 10/17 (59%) improved; the longest time to response was 3–4 months 32 patients (8 months to 64 years old) with atopic dermatitis 2 g/kg per month for 1 to 11 cycles, 1 patient with WAS 1 g/kg per month for 1 month; 14/32 patients received IVIg as monotherapy, 5 patients Bayer Biological Co., 6 patients Flebogamma®, 10 patients Venoglobulin I ®, 3 patients Sandoglobulin®/Alphaglobulin®, 8 patients preparation NA Review of published case reports [ 304 ] 9 of 10 patients responded: 3 patients with complete remission sustained 3 years later; 2 patients with temporary complete remission; 4 patients improved subsequent to treatment; total urticaria activity score assessed by physician and by patient with the use of visual analog score at 2 and 6 weeks improved significantly ( p < 0.01) without significant change of the positivity of autologous serum injection test 10 patients with severe chronic autoimmune urticaria 0.4 g/kg per day for 5 days as 3% solution in normal saline on the first day, followed by a 6% solution on the succeeding 4 days (Sandoglobulin®, Novartis, UK); sympatientomatic treatment with cetirizine 20 mg/day was taken by all patients Case series [ 305 ] Chronic urticaria After the 1st application of IVIg, urticaria score was reduced to 1, maintained with repeated administrations of IVIg in intervals of 4 weeks A 63-year-old woman with a 2-year history of chronic urticaria with urticaria score of 4/8 despite H1-and H2-blockers Low-dose IVIg 0.2 g/kg every 4 weeks adjunctive to standard antihistamine therapy Case report [ 306 ] 95% resolution over 3.5 months without concomitant therapy A 28-year-old female with 41-month history of severe chronic urticaria 1 cycle of Venoglobulin® 2 g/kg in 5 days as monotherapy Case report [ 280 ] 5 of 8 responded: 3 remission (2 after one and 1 after 3 cycles); 2 patients improved; responders improved with 3 or fewer infusions; 3 patients failed to improve after 2–6 cycles of IVIg; ASST was not a predictor of response to IVIg 8 adult patients with steroid-dependent refractory delayed pressure urticaria (concomitant with chronic urticaria 8/8, angioedema 4/8, cholinergic urticaria 1, and dermographism 1) 2 g/kg per month (Scottish National Blood Transfusion Service) over 2 to 3 days, followed by antihistamines and CS Uncontrolled trial [ 307 ] Delayed pressure urticaria After 3 cycles tolerated visible light and 15 min of intense solar exposure, SU has disappeared after 1 year 55-year-old woman suffered from resistant solar urticaria for 3 years IVIg Case report [ 308 ] Solar urticaria Optimal improvement with combination of IVIg, antihistamines, and PUVA A female patient with resistant solar urticaria IVIg 2.5 g/kg over 3 days Case report [ 309 ] Taper off of CS and prolonged remission; recurrence and remission of symptoms were associated with changes of IVIg lot and source A 54-year-old man IVIg 0.4 g/kg every 3 weeks (Panglobulin® or Gamimune N® according to availability) adjunctive to CS Case report [ 310 ] Angioedema with hypereosinophilia syndrome 2 patients experienced dramatic improvement in both their joints and skin and a fall in inflammatory markers; 1 patient had improvement in arthritis but little change in skin involvement 3 patients with treatment-resistant psoriasis and psoriatic arthritis IVIg (Octagam®, Octapharma, Coventry, UK) 2 g/kg over 3 to 4 days adjunctive to conventional treatment; in 2 cases, improvement was sustained with additional cycles of IVIg; in 1 case, information is not available Case series [ 311 ] Psoriasis 7 of 10 patients demonstrated clearance of lesions; in 6/7 of cases, the efficacy maintained with repeat IVIg infusions 10 patients with severe refractory pyoderma gangrenosum IVIg 2 g/kg per month in 3 days, 9/10 in conjunction with CS and MMF and/or cyclosporin; IVIg was stopped after 2 to 3 cycles in case of ineffectiveness Case series [ 312 ] Pyoderma gangrenosum Stabilization of pyoderma gangrenosum and steroid-sparing effect in both patients Case 1 with a 6-year and case 2 with a 3-year history of multidrug-resistant pyoderma gangrenosum IVIg 2 g/kg per month for 6 months adjunctive to CS Case report [ 313 ] Improvement of range of joints motion and laxity of skin after 1 month but no further improvement after the 2nd and the 3rd cycles of IVIg A 61-year-old male with a 4-month history of NFD IVIg 2 g/kg in 5 days for 3 months Case report [ 314 ] Nephrogenic fibrosing dermopathy Clinical improvement in all patients after 2–9 months with reduction of skin thickness by US evaluation (4/7), reduction of mucopolysaccharide skin content (3/7), disappearance of lymphocytic skin infiltration and IgG deposition (2/7) 7 patients affected by Grave's ophthalmopathy and pretibial myxedema IVIg Endoglobulin® 2 g/kg every 3 weeks as monotherapy Case series [ 315 ] Pretibial myxedema 8 patients had complete (2) or partial (6) response, but in all the effect was transient, requiring reinfusion and maintenance therapy 10 patients with scleromyxedema—8 cases proven by skin biopsy, 2 had inconclusive biopsy results but had classic clinical findings and a characteristic gammopathy IVIg in dose 0.4–1.0 g/kg per day for 2–5 days for a total 2 g/kg every month for 6 months as monotherapy after failure of other treatment modalities Case series [ 316 ] Arndt–Gottron scleromyxedema All patients had cutaneous improvement as well as improvement in ureteral stricture, vocal strength, and dysphagia 3 patients with scleromyxedema IVIg 0.4 g/kg per day for 5 days every 5 weeks (Gammagard; Baxter Healthcare Corp, Hyland Immuno, Glendale, CA, USA) Case report [ 317 ] First patient had significant reduction in skin scores (36/60 to 11/60) for 1 year only; second had a dramatic sustained response with continued Tx (interval subsequently increased to 10 weeks) 2 patients with scleromyxedema and severe skin disease IVIg 0.4 g/kg per day for 5 days, monthly Case report [ 318 ] Improvement after the first treatment, continuous skin softening and reduction of induration, sustained response to treatment after 20 courses A 48-year-old female with long-standing scleromyxedema unresponsive to high-dose CS and immunosuppressive (CP, melphalan) treatment IVIg 2 g/kg in 2 days (Intratect®; Biotest, Dreieich, Germany) every 4 weeks, adjunctive to PD 10 mg/day Case report [ 319 ] Progressive clinical improvement over several months allowing discontinuation of PD but rapid deterioration afterwards with lethal CVA despite reinstating PD and CP An 81-year-old female with scleromyxedema and IDDM IVIg (Gamimune N, 10%, Bayer) 1.5 g/kg (dose reduced due to CHF) every 4 weeks and oral PD 30 mg/day Case report [ 320 ] A positive response after 2 cycles An 82-year-old female with a 12-year history of scleromyxedema unresponsive to various preceding therapies Venimmun® N (ZLB Behring, Germany) 0.5 g/kg for 5 days at 4-week intervals as monotherapy Case report [ 321 ] Marked clinical improvement, maintained with repeated IVIg infusions A 56-year-old woman with scleromyxedema IVIg (Sandoglobulin®) 2 g/kg over 5 days as monotherapy Case report [ 322 ] Complete clearance of skin lesions, sustained effect after 1 year without treatment A 47-year-old female with 8-year history of tumorous variant of scleromyxedema and a history of ineffectiveness of melphalan and PD therapy 5 courses of IVIg 0.3 g/kg for 5 days every 4 weeks adjunctive to melphalan 4–2 g/day and PD 30–10 mg/day, 5 additional cycles as monotherapy 1 year later Case report [ 323 ] Improvement in all but relapse in 1 patient, 2 weeks to 6 months for full response, most needing 6–8 weekly cycles 10 patients, 30–79 years old with scleromyxedema IVIg 2 g/kg per month given over 5 days; Octagam® (2 patients), Sandoglobulin® (3 patients), Gammagard ®SD (1 patient), unknown (2patients); adjunctive to PD (2 patients) and thalidomide (1 patient) or as monotherapy (7 patients) Review of published case reports [ 324 ] Regrowth of eyelashes, eyebrows, and body and scalp hair after second dose, significant hair re-growth with 5–6 cm of scalp hair 8-year-old girl with CVID and alopecia universalis IVIg 0.4 g/kg every 4 weeks Case report [ 325 ] Alopecia universalis

Autoimmune blistering diseases

Pemphigus vulgaris

Level of evidence B

There is some evidence that IVIg have steroid-sparing effect and may be effective as monotherapy and/or adjunctive therapy in patients with previously severe unresponsive pemphigus vulgaris ( strength of recommendation IIa ).

Pemphigus foliaceus

Level of evidence C

Adjunctive to standard immunotherapy treatment with IVIg may cause improvement in clinical course and may have steroid-sparing effect in previously steroid-dependent patients with refractory pemphigus foliaceus ( strength of recommendation IIa ).

Bullous pemphigoid

Level of evidence C

In some severe cases of bullous pemphigoid, IVIg was found to be effective as monotherapy and adjunctive therapy as well; it had steroid-sparing effect and led to improvement of quality of life ( strength of recommendation IIa ).

Mucous membrane pemphigoid

Level of evidence C

There is some evidence that IVIg monotherapy may be at least as effective as standard immunosuppressive treatment and lead to quick therapy response and better quality of life ( strength of recommendation IIa ).

Epidermolysis bullosa acquisita, linear IgA disease, pemphigoid gestationis

Level of evidence C

The sparse data of positive effect of IVIg on severe cases of epidermolysis bullosa acquisita, linear IgA disease, and pemphigoid gestationis were published ( strength of recommendation IIa ).

Summary

In autoimmune blistering diseases, the treatment with IVIg may be effective and has to be implicated in cases with severe disease, resistant to conventional therapy or those who experienced severe complications of such therapy.

Other immune-mediated dermatoses

Stevens–Johnson syndrome and toxic epidermal necrolysis

Level of evidence C

The randomized studies have not been performed and the current knowledge about effectiveness of IVIg in SJS and TEN is based on results of multiple prospective noncontrolled studies, retrospective case series, and case reports. The data are limited and inconclusive ( strength of recommendation IIb ).

Atopic dermatitis

Level of evidence B

The current data based on single, randomized, controlled, and evaluator-blinded trial and number of prospective noncontrolled studies suggest that IVIg may be effective as monotherapy in pediatric patients and as adjunctive therapy in adults. However, in view of the low-cost effectiveness of IVIg, this treatment should be used in cases of severe disabling atopic dermatitis ( strength of recommendation IIa ).

Urticaria

Level of evidence C

A number of case reports and case series describe the beneficial effect of IVIg in chronic idiopathic and autoimmune urticaria, but randomized controlled studies are still lacking. The use of IVIg has to be limited to severe unresponsive cases of chronic urticaria or in case of severe complications of conventional treatment ( strength of recommendation IIa ).

Psoriasis

Level of evidence C

Only three cases of severe resistant psoriasis with psoriatic arthritis responsive to treatment with high-dose immunoglobulin were reported. We conclude that there is now evidence of effectiveness of IVIg in psoriasis ( strength of recommendation IIb ).

Pyoderma gangrenosum

Level of evidence C

IVIg was successfully used in few cases of previously unresponsive pyoderma gangrenosum, but its systematic use cannot be recommended ( strength of recommendation IIa ).

Miscellaneous dermatoses

Level of evidence C

Several case reports and case series showed IVIg to be effective for nephrogenic fibrosing dermopathy, pretibial myxedema, and Arndt–Gottron scleromyxedema, but still well-controlled studies are lacking. We suppose that IVIg can be used in severe cases of these rare conditions, unresponsive to conventional treatment ( strength of recommendation IIa ; Table 10 ). Table 10 The use of intravenous immunoglobulins in oncological diseases Results/response Number of patients Intervention including dose and IVIg preparation used Study design Ref. Disease Considerable improvement of KS skin lesions after 2 weeks, disappearance of 6 of 8 skin lesions after 1 month; after 3 cycles, only 1 remnant skin lesion; after 2 years of monthly treatment, no relapse of KS or progression of polymyositis 45-year-old patient with polymyositis, who developed KS when given immunosuppressive therapy for polymyositis IVIg 0.4 g/kg per day for 5 days (Sandoglobulin®, Sandoz, Switzerland) adjunctive to low-dose PD Case report [ 326 ] Kaposi's sarcoma (KS) 2 of 9 (22%) patients had stabilization of disease (one for 8 months) 9 patients with metastatic melanoma IVIg 1 g/kg (VIGAM® LIQUID, BPL, UK, contains 0.5 g sucrose per gram of immunoglobulin) given over a 1- to 3-day period at a maximum dose of 25 g/day for up to 8 h, every 3 weeks (during 3 or 6 months in case of nonprogression according to CT/MRI) adjunctive to standard therapy Uncontrolled trial [ 327 ] Metastatic melanoma No mucositis after MTX treatment followed by IVIg in both cases 15-year-old male and a 5-year-old girl, who developed grade 3 mucositis after every course of MTX 0.2 g IVIg/kg applied 27 h after the 24-h MTX infusion Case report [ 328 ] Chemotherapy-induced oral mucositis Complete remission of thymoma after 4 cycles of IVIg confirmed by FDG-PET A patient with metastatic malignant thymoma and myasthenic crisis IVIg Case report [ 329 ] Thymus carcinoma Case 1 developed immunodeficiency 2 years after the resection of thymoma, maintained with IVIg and low-dose CS; case 2 was maintained with IVIg and was stable but developed Kaposi sarcoma 3 years afterwards Case 1—a 51-year-old woman Monthly IVIg 0.4 g/kg Case report [ 330 ] Thymoma and immunodeficiency (Good syndrome) Case 2—an 89-year-old man

Kaposi's sarcoma

Level of evidence C

A patient with polymyositis and Kaposi sarcoma had remission of both conditions on IVIg therapy ( strength of recommendation IIb ).

Metastatic melanoma

Level of evidence C

Stabilization of metastatic melanoma was shown in the small group of patients after addition of IVIg to standard therapy ( strength of recommendation IIb ).

Chemotherapy-induced oral mucositis

Level of evidence C

IVIg was shown to be effective in preventing severe recurrent chemotherapy-induced oral mucositis in two patients treated with methotrexate ( strength of recommendation IIa ).

Thymus carcinoma

Level of evidence C

Anecdotal case report describes complete remission of metastatic malignant thymoma after four cycles of IVIg given to myasthenic patient ( strength of recommendation IIb ).

Thymoma and immunodeficiency (Good syndrome)

Level of evidence C

After thymectomy, two patients with Good syndrome were maintained with IVIg for developed immunodeficiency; one of them developed Kaposi sarcoma after 3 years ( strength of recommendation IIb ; Table 11 ). Table 11 The use of intravenous immunoglobulins in endocrine disorders Results/response Number of patients Intervention including dose and IVIg preparation used Study design Ref Disease 21 of 26 patients showed improvement of the mean Neuropathy Impairment Score (NIS) from 61.5 ± 26.0 to 33 ± 29.6 ( p < 0.001); improvement of NIS was more frequent in patients with a conduction block (100%) vs. in those who did not (66.7%; p = 0.03); relapses occurred less in the responders who had a conduction block (9.1%) vs. in those who did not (50%; p = 0.04) 26 patients with DDP evaluated at baseline, at the end of 4 weeks of IVIg therapy, afterwards every few months, mean follow-up period of 25 months. IVIg 0.4 g/kg for 5 days Prospective open label [ 331 ] Diabetic demyelinating polyneuropathy Reached 80% reduction of pains and significant recovery of muscle strength A 57-year-old man with type 2 diabetes and painful proximal diabetic neuropathy with muscle weakness and atrophy IVIg 0.4 g/kg for 5 days Case report [ 332 ] Proximal diabetic neuropathy All defective cranial nerve findings disappeared during the 1st month and did not recur during 8 months of follow-up A 55-year-old woman, with 12-year history of DM, developed simultaneous right VII and left III, IV, and VI cranial nerve pulses IVIg 0.4 g/kg for 5 days Case report [ 333 ] Cranial nerve neuropathy in diabetes mellitus 5 days after IVIg easy fatigability of thigh disappeared and of the strength of shoulder girdle muscle improved; 1 year after IVIg treatment, there was normal muscle strength and significant improvement of atrophy A 45-year-old man with IDDM and diabetic amyotrophy IVIg 0.4 g/kg per day for 5 days Case report [ 334 ] Diabetic amyotrophy Rapid improvement of fasting serum glucose levels, stabilization of renal function, and decrease in the donor-specific class II antibodies A 44-year-old man with long-standing poorly controlled IDDM 3 doses of 0.5 g/kg per day of IVIg, started on day 14 posttransplant and given every other day adjunctive to standard posttransplant therapy, plasmapheresis, and rituximab Case report [ 335 ] Pancreas allograft rejection Partial response to IVIg and complete resolution of weakness after CP, asymptomatic after 1 year without treatment A 17-year-old man with known IDDM and a subclinical Hashimoto's thyroiditis and a new onset of asymmetric weakness and atrophy in arms Monthly infusions of IVIg 0.4 g/kg per day for 5 consecutive days followed by 6 cycles of CP 1 g/m 2 Case report [ 336 ] Multifocal motor neuropathy, type 1 diabetes, and Hashimoto's thyroiditis Within 10 weeks after IVIg, muscle weakness and sensory disturbances disappeared, but tendon reflexes stayed slightly depressed; the patient was treated with IVIg every 3 months due to IVIg-dependent course A 64-year-old man with clinical and laboratory findings supportive for MMN, high titers of anti-GM1-Abs and subclinical Hashimoto's thyroiditis IVIg 0.4 g/kg per day for 5 days, repeated every 3 months due to IVIg-dependent course of the disease Case report [ 337 ] Multifocal motor neuropathy and Hashimoto's thyroiditis Partial response to CS and IVIg and antiepileptic medication (probably due to lowering of seizure threshold by antithyroid drugs and beta-blockers); continued with immunosuppressive therapy (high-dose CS and AZA) but relapsed after 2 months, recovered after thyroidectomy A 34-year-old woman with encephalopathy and thyrotoxic Hashimoto's thyroiditis IVIg 2 g/kg in 3 days adjunctive to high-dose CS and plasmapheresis Case report [ 338 ] Thyrotoxic autoimmune encephalopathy See ophthalmology section Grave's ophthalmopathy All had normalization of VLCFA within 3 months, but neurological status continued to deteriorate in both groups 6 of 12 patients with X-linked childhood and adolescent adrenoleukodystrophy received IVIg in addition to diet and GTOE supplement IVIg 1 g/kg in 8–12 h (Gamma globulin; Merieux, France) every 15 days for 3 months and every month for a year, thereafter; both groups received very-long-chain fatty acids (VLCFA)-restricted diet and supplement of 40 mg/day glycerol trioleate and erucic acids (GTOE) RCT [ 339 ] Adrenoleukodystrophy 3/9 improved; 3/9 remained stable; 3/9 deteriorated and died 9 adult patients with various X-ALD phenotypes 15 cycles of 1 g/kg 7 S-immunoglobulin (Venimmun, Behring, Germany) Uncontrolled trial [ 340 ] Recovery of adrenal function but dependence on dialysis 18 months later A 20-year-old man with Waterhouse–Friderichsen syndrome and bilateral renal cortical necrosis secondary to meningococcal sepsis Neither protocol nor IVIg preparation is available; IVIg adjunctive to aggressive treatment with antibiotics, CS, vasopressors, plasmapheresis, and dialysis Case report [ 341 ] Waterhouse–Friderichsen syndrome During IVIg treatment, normalization of thyroid function, some nonovulatory menses, and reduction of antibody titers were observed A female with autoimmune polyendocrine syndrome type 2 IVIg Case report [ 342 ] Autoimmune polyendocrine syndrome

Summary

There are still no randomized controlled trials evaluating efficacy of IVIg and it cannot be recommended for treatment of epithelial or other solid malignancies.

Diabetes mellitus

Level of evidence C

There is some evidence that IVIg therapy can improve the Neuropathy Impairment Score in patients with diabetic demyelinating polyneuropathy ( strength of recommendation IIa ). A few case reports describe regression of symptoms of proximal diabetic neuropathy, diabetic amyotrophy, and cranial nerve neuropathy in different diabetic patients treated with IVIg ( strength of recommendation IIa ). We conclude that evidence for the use of IVIg in diabetic neuropathies is poor and its systematic use cannot be recommended.

Hashimoto's encephalopathy

Level of evidence C

A rare case of autoimmune encephalopathy during thyrotoxic phase of Hashimoto's disease only partially responded to immunosuppressive therapy with adjuvant intravenous immunoglobulin ( strength of recommendation IIb ).

X-linked adrenoleukodystrophy

Level of evidence B

Therapeutic efforts including dietary therapy and immunomodulation with IVIg fail to improve prognosis in patients with X-linked adrenoleukodystrophy and BMT remains the only treatment that can reverse early neurological manifestations and adrenal impairment of ALD ( strength of recommendation III ).

Waterhouse–Friderichsen syndrome

Level of evidence C

No evidence supports the use of IVIg in Waterhouse–Friderichsen syndrome due to meningococcal sepsis ( strength of recommendation III ).

Autoimmune polyendocrine syndrome

Level of evidence C

No evidence supports the use of IVIg in autoimmune polyendocrine syndrome type 2 ( strength of recommendation IIb ; Table 12 ). Table 12 The use of intravenous immunoglobulins in neurological diseases Disease Ref. Study design Intervention including dose and IVIg preparation used Number of patients Results/response Opsoclonus myoclonus [ 343 ] Case reports IVIg 3 doses of 0.3 g/kg over 4 months + rituximab 2 patients with postinfectious opsoclonus myoclonus syndrome Significant clinical improvement without relapses [ 344 ] Case report IVIg 0.4 g/kg per day for 5 days + prednisolone + clonazepam A 41-year-old woman with idiopathic opsoclonus myoclonus syndrome Complete recovery [ 345 ] Case report IVIg 30 g/day for 5 days with 5 repeated doses after 2 months + CS A 36 year-old man with parainfectious opsoclonus myoclonus syndrome Accelerated recovery [ 346 ] Case report IVIg + ACTH + CS A patient with childhood-onset opsoclonus myoclonus Partial recovery [ 347 ] Case report IVIg initially 5.5 g and 6 additional courses at a dosage of 2.5 g and 7 courses at a dosage of 5 g every 2 to 3 weeks + ACTH A 22-month-old girl with neuroblastoma-associated opsoclonus myoclonus Partial recovery [ 348 ] Case report IVIg + ACTH A 27-year-old woman with severe opsoclonus myoclonus Complete recovery [ 349 ] Case report IVIg 1 g/kg for 2 days with 12 additional doses given every 4–6 weeks An 18-month-old black girl with neuroblastoma-associated opsoclonus myoclonus Complete recovery [ 350 ] Case report High-dose IVIg A 14-month-old male with infantile opsoclonus myoclonus Complete recovery [ 351 ] Retrospective study IVIg + CS 9 patients with idiopathic and paraneoplastic opsoclonus myoclonus Idiopathic opsoclonus myoclonus: 2/9 complete recovery, 1/9 partial recovery, 2/9 remission Paraneoplastic opsoclonus myoclonus: 3/9 no response, 1/9 partial recovery PANDAS [ 352 ] RCT IVIg I g/kg per day for 2 days vs PP vs placebo 29 children with severe infection-triggered exacerbations of obsessive-compulsive disorder (OCD) or tic disorders, including Tourette syndrome At 1 month, significant improvement in global impairment ( p = 0.0009), obsessive- compulsive symptoms ( p = 0.006), anxiety ( p = 0.001), depression (0.002); at 1 year, more than 80% of patients receiving IVIg or PP remained improved Multiple sclerosis (MS) [ 353 ] RCT IVIg 0.2 g/kg–0.4 mg/kg every 4 weeks for 48 weeks vs placebo 127 patients with relapsing–remitting multiple sclerosis (RRMS) At 1 year, there was no significant difference in the proportion of relapse-free patients among treated groups [ 354 ] RCT (primary and secondary chronic progressive MS) IVIg 0.4 g/kg per month for 24 months vs placebo 231 patients with primary (PPMS) and secondary (SPMS) chronic progressive MS IVIg can delay progression of disease in primary chronic progressive MS; no significant difference in progression was noted for secondary chronic progressive MS; no improvement in neurological functions with IVIg [ 355 ] RCT (secondary progressive MS) Monthly IVIg 1 g/kg for 27 months vs placebo 34 patients with secondary progressive (SP) MS No reduction in the relapse rate or the progression of disability [ 356 ] Retrospective study (relapsing–remitting MS) IVIg treatment at a mean time of 3.4 ± 1.8 years at a mean dose of 15.5 ± 8.3 g/month 308 patients with RRMS 69% reduction of mean annual relapse rate was observed after IVIg treatment initiation [ 357 ] RCT (secondary progressive MS) IVIg 1 g/kg per month for 27 months vs placebo 318 patients with secondary progressive multiple sclerosis No effect on the time to confirmed progression on the EDSS, annual relapse rate, and the change in T2 lesion load on MRI [ 358 ] Meta-analysis IVIg 0.15–2 g/kg for 12–24 months vs placebo 4 RCT (265 patients with RRMS) Significant beneficial effect: on the annual relapse rate ( p = 0.00003), on the proportion of relapse-free patients ( p = 2.1 × 10 −8 ) [ 359 ] RCT IVIg 0.15–0.2 g/kg per month for 2 years vs placebo 148 patients with RRMS Progression of disability was reduced in 24% of the patients with therapeutic efficacy to be noted in the first 6 months of the treatment [ 360 ] RCT (relapsing remitting MS) IVIg 0.4 g/kg for 5 days followed by once every 2 months for 2 years vs placebo 40 patients with RRMS Reduction in yearly exacerbation rate ( p = 0.0006 (overall)) [ 361 ] RCT (relapsing remitting MS) IVIg 1 g/kg for 2 days every 4 weeks for 24 weeks vs placebo 17 patients with relapsing–remitting or relapsing progressive multiple sclerosis 11 had no exacerbations during IVIg treatment compared with only 6 on placebo ( p = 0.05) Guillain–Barré syndrome (GBS) [ 362 ] Systematic review meta-analysis IVIg 0.2–1 g/kg per day for 2–6 days vs PP vs immunoabsorption vs supportive care 11 RCT (913 patients) Improvement on the disability grade scale with intravenous immunoglobulin (IVIg), weighted mean difference WMD of 0.02 (95% confidence interval (CI) 0.25 to 0.2); no significant difference between IVIg and plasma exchange [ 363 ] Open-labeled study IVIg 0.4 g/kg per day for 5 days 11 patients younger than 15 years old, diagnosed with moderate or severe GBS After 2 weeks, 72.7% of patients improved by one or more grades and 36.4% improved by 2 or more grades, measured on the Hughes' functional grade FG scale After 4 weeks, 81.8% of patients improved by one or more grades and 63.6% of patients improved by 2 or more grades [ 364 ] RCT IVIg 0.4 g/kg per day for 3 or 6 days 39 patients with Guillain–Barré syndrome No significant difference in time to assisted walking in the 2 groups ( p = 0.08); significantly shorter time to assisted walking in ventilated patients in the 6-day group ( p = 0.04) [ 365 ] RCT (IgG anti-GM1-positive subgroup) IVIg vs plasmapheresis 24 patients with Guillain–Barré syndrome IVIg-treated patients had: significantly lower Hughes grade scores 1, 3, and 6 months after onset ( p = 0.03); higher probability to regain independent locomotion at 6 months ( p = 0.044); more frequent rapid recovery within 4 weeks ( p = 0.03) Plasma exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group [ 366 ] RCT IVIg 0.4 g/kg per day for 5 days vs plasma exchange 379 adult patients with Guillain–Barré syndrome IVIg is equivalent to plasmapheresis in reducing the amount of disability at 4 weeks after treatment [ 367 ] RCT IVIg 0.4 g/kg per day for 5 days vs plasma exchange 150 patients with Guillain–Barré syndrome 53% of patients treated with IVIg improved compared to 34% in the PP group ( p = 0.024) Paraproteinemic neuropathy (IgM) [ 368 ] Systematic review IVIg or interferon alpha or plasma exchange 5 trials (97 patients with IgM antimyelin-associated glycoprotein paraproteinemic neuropathy) 2 trials with 33 patients suggest that IVIg may sometimes produce short-term benefit (in terms of improvement in Modified Rankin Scale at 2 weeks and 10-m walk time at 4 weeks) and is relatively safe [ 369 ] Crossover RCT IVIg 2 g/kg over 1 to 2 days vs placebo 22 patients with paraproteinemic demyelinating neuropathy After 4 weeks, the overall disability significantly decreased during the IVIg period ( p = 0.001) compared to the placebo period where it was unchanged; the mean difference between the treatment effects was significant ( p = 0.05) [ 370 ] Crossover RCT IVIg vs placebo given monthly for 3 months 11 patients with demyelinating polyneuropathy associated with monoclonal IgM antibodies Modest benefit with IVIg Amyotrophic lateral sclerosis [ 371 ] Case series IVIg 0.4 g/kg per day for 5 days followed by monthly 2-day infusions + CP 7 patients with amyotrophic lateral sclerosis All patients worsened according to MRC and/or bulbar and/or Rankin scores [ 372 ] Case series IVIg monthly for 3 months 9 patients with rapidly progressive amyotrophic lateral sclerosis All patients worsened after 3 months with decrease in mean total muscle scores (megascores) Lambert–Eaton myasthenic syndrome [ 373 ] Crossover RCT IVIg 1 g/kg per day for 2 days vs placebo 9 with Lambert–Eaton myasthenic syndrome IVIg showed significant improvements in limb, respiratory, and bulbar muscle strength measures ( p = 0.017 to 0.038) and a significant decline in serum calcium channel antibody titers ( p = 0.028) Stiff person syndrome [ 374 ] Case series IVIg 3 patients with active disease and/or disease refractory to treatment with diazepam and/or CS Improvement after treatment [ 375 ] Uncontrolled pilot study IVIg 3 patients with stiff-man syndrome Improvement after treatment [ 376 ] Case report IVIg A patient with refractory stiff-man syndrome Long-term remission after treatment [ 377 ] Crossover RCT IVIg 2 g/kg once a month for 3 months vs placebo 14 patients with stiff-person syndrome and anti-GAD65 antibodies According to stiffness scores, IVIg was superior compared to placebo in direct treatment effect ( p = 0.01) and in first-order carryover effect ( p = 0.001) Adrenoleukodystrophy [ 378 ] RCT IVIg 1 g/kg per day every 15 days for 3 months and every month for 1 year + VLCFA-restricted diet + GTOE vs VLCFA-restricted diet + GTOE 12 X-linked adrenoleukodystrophy No significant differences in deterioration of neurological symptoms in the 2 groups according to EDSS score Intractable childhood epilepsy [ 379 ] RCT IVIg 0.1–0.4 g/kg (7 infusions in 6 weeks total time) vs placebo 61 patients with refractory epilepsy (46 with partial epilepsy) No significant difference between the groups studied; no relationship between IVIg dose and efficacy [ 380 ] Crossover RCT IVIg 0.4 g/kg (Sandoglobulin) 2 infusions each with an interval of 2 weeks vs placebo 10 patients aged 4–14 years with Lennox–Gastaut syndrome 2/10: immediate reduction in their high-frequency and invariable seizure activity from 42% to 100% and a less abnormal EEG 8/10: unchanged general condition, no EEG changes Critical illness polyneuropathy [ 381 ] Retrospective chart analysis IVIg 0.3 g/kg per day for 3 days 16 patients with critical illness polyneuropathy following multiple-organ failure and gram-negative sepsis 8/16 patients of MOF with sepsis without the development of CIP had been treated with IVIg immediately after the diagnosis of sepsis 7/16 who eventually developed CID were not treated with IVIg [ 382 ] Case series IVIg 3 patients with critical illness polyneuropathy No improvement after treatment Rasmussen's encephalitis [ 383 ] Case series IVIg, CS, CP, therapeutic PP (TPE), protein A, immunoglobulin G (IgG), immunoadsorption (PAI) 15 patients with Rasmussen encephalitis (14 with childhood and one with adolescent onset) In 11 patients treated with IVIg, 1 had reduction of seizure frequency by >50% and improvement of neurologic condition or resolution of status epilepticus and 2 had reduction of seizure frequency by up to 50%; in the rest, 5 had no effect and in the 3 effect was not assessable [ 384 ] Case report IVIg 0.4 g/kg per day for 5 days once a month A 45-year-old woman with adult-onset Rasmussen encephalitis Improvement after IVIg therapy with a >75% reduction in seizures and mild improvement in neurologic performances [ 385 ] Case reports IVIg 0.4 g/kg per day for 5 days once a month 2 patients with advanced adult-onset Rasmussen's encephalitis Significant improvement in seizure control, hemiparesis, and cognition [ 386 ] Case series IVIg ± high-dose CS 19 patients with Rasmussen's encephalitis 8/9 patients receiving IVIg had some reduction of seizure frequency and mild improvement in hemiparesis Chronic inflammatory demyelinating polyradiculoneuropathy [ 387 ] Crossover RCT IVIg 1 to 2 g/kg over 1 to 2 days every 3 weeks for 24 weeks vs placebo 117 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 54% of patients treated with IVIg and 21% treated with placebo improved according to INCAT disability score ( p = 0.0002); IVIg patients had a longer relapse time compared with placebo ( p = 0.011) in the extension phase [ 388 ] Crossover RCT IVIg 2 g/kg over 1 to 2 days vs oral prednisolone for 6 weeks 24 patients with CIDP Both treatments showed marked improvement in INCAT disability scores after 2 weeks; no significant difference between the 2 treatments [ 389 ] RCT IVIg 1 g/kg per day for 2 days vs placebo 53 patients with untreated CIDP Average muscle score (AMS) was significantly improved in the IVIg group ( p = 0.0006) at day 42; IVIg significantly improved nerve conduction; according to Hughes’ functional disability scale IVIg group showed better improvement than placebo ( p = 0.019) [ 390 ] Crossover RCT IVIg 0.4 g/kg per day for 5 days vs placebo 30 patients with definite or probable CIDP of chronic progressive (16 patients) or relapsing (14 patients) course At 4 weeks, significant improvement with IVIg in neurological disability score (NDS; P < 0.0001) in clinical grade (CG; P < 0.002) and in grip strength (GS; P < 0.001); significant improvement in summed MCV ( P < 0.0001) and in summed (CMAP) amplitudes ( P < 0.03) Myasthenia gravis [ 391 ] Systematic review IVIg vs no treatment or placebo or plasma exchange 6 RCT ( n = 371) There is insufficient evidence to determine the efficacy of IVIg in myasthenia gravis [ 392 ] RCT IVIg 2 g/kg over 2 days vs placebo 51 patients with worsening weakness due to myasthenia gravis According to quantitative myasthenia gravis (QMG) score at day 14, there was a significant improvement in the IVIg group ( p = 0.047) which continued at day 28 [ 393 ] RCT IVIg 2 g/kg vs placebo 15 patients with myasthenia gravis No significant differences between the 2 groups were noted at day 42 according to QMG score [ 394 ] Crossover RCT IVIg 0.4 g/kg for 5 days vs plasma exchange 12 patients with generalized moderate to severe myasthenia gravis on immunosuppressive treatment for at least 12 months After 1 and 4 weeks of treatment, a significant improvement was noted according to QMG score in both groups; no significant difference between them [ 395 ] Case series IVIg 0.04 g/kg per day for 5 days and maintenance every 6 weeks 10 patients with severe generalized myasthenia and an acute deterioration unresponsive to conventional therapy Significant improvement according to Osserman scale at 1 year ( P < 0.001) in all patients Acute disseminated encephalomyelitis [ 396 ] Case report IVIg 2 g/kg once and repeat bolus of 150 g on week 3 and 4; previews treated with CS with no response A 20-year-old male with postvaccination acute disseminated encephalomyelitis Rapid response with partial recovery over 1 year [ 397 ] Case series IVIg 2 g/kg over 2 days or MP or IVIg 2 g/kg over 2 days + MP 16 children with severe acute disseminated encephalomyelitis 1 patient treated with IVIg and 10 patients treated with CS alone had complete response; from 5 patients treated with combined therapy, 2 had complete response and 3 partial or no response [ 398 ] Case series IVIg 0.4 g/kg per day for 5 days 5 adult patients, 3 of them affected by classic disseminated encephalomyelitis and 2 by a postinfectious myelitis Marked functional improvement in all patients starting from day 5 with maximum effect at 3 weeks [ 399 ] Case report IVIg + CS for 3 days A child with atypical acute disseminated encephalomyelitis Complete response [ 400 ] Case report IVIg + CS A 3-year-old boy with severe acute disseminated encephalomyelitis Complete response [ 401 ] Case reports IVIg 30 g/day for 5 days and 3 additional monthly courses of 30 g + CS 2 adult women with acute disseminated encephalomyelitis Complete response in both patients IVIg 50 g/d for 2 days + CS. Autism [ 402 ] Case series IVIg 0.04 g/kg monthly for 6 months 7 patients with childhood autism No statistically significant changes on behavioral measures after 6 months PANDAS pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections

Acute disseminated encephalomyelitis

Level of evidence C

There is weak evidence coming out from several case reports that IVIg may be a useful treatment option either as a combination therapy with CS or in cases that steroid treatment fails ( strength of recommendation I ).

Adrenoleukodystrophy

Level of evidence B

Taking into consideration the limited evidence (one RCT) and the unfavorable effect of IVIg treatment, at this point, IVIg should not be used as treatment of adrenoleukodystrophy ( strength of recommendation III ).

Amyotrophic lateral sclerosis

Level of evidence C

No benefit was observed from the use of IVIg in two case series. Considering the weak evidence and the negative outcome, IVIg is not recommended for the treatment of amyotrophic lateral sclerosis ( strength of recommendation III ).

Autism

Level of evidence C

The use of IVIg in autism is only limited to case series and the effect is questionable. IVIg is not recommended at the moment for the treatment of autism ( strength of recommendation III ).

Chronic inflammatory demyelinating polyneuropathy

Level of evidence A

Several RCTs evaluated the effectiveness of IVIg. The results of these studies are strongly pointing to the useful effect of IVIg in patients with chronic inflammatory demyelinating polyneuropathy. IVIg should be considered as an additional option in combination with other immunosuppressive agents ( strength of recommendation I ).

Opsoclonus myoclonus

Level of evidence C

In this rare syndrome, IVIg was reported in several case reports and a retrospective study proved that it induced significant response. Although there is no strong evidence, IVIg may be considered as an additional option in treatment of opsoclonus myoclonus ( strength of recommendation I ).

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections PANDAS

Level of evidence B

Results coming from one small RCT testing the effect of IVIg showed significant improvement in symptoms; therefore, IVIg is recommended as an additional option for treatment of PANDAS ( strength of recommendation I ).

Multiple sclerosis

Level of evidence A

Data from several RCTs and a meta-analysis showed significant differences between IVIg and placebo favoring the use of IVIg in relapsing–remitting multiple sclerosis (MS). On the other hand, a recent RCT including 127 with relapsing–remitting MS treated with IVIg or placebo showed no significant difference in the proportion of relapse-free patients among treated groups. Another recent RCT including 231 patients showed that IVIg can delay progression of disease in primary chronic progressive MS but no significant difference in progression was noted for secondary chronic progressive MS. To conclude, IVIg may be used as an alternative therapy in relapsing–remitting MS and in primary chronic progressive MS when standard immunosuppression therapy fails ( strength of recommendation IIb ).

Guillain–Barré

Level of evidence A

There is strong evidence, several randomized controlled trials, and a meta-analysis that prove that IVIg is of benefit in improving the disability grade in patients with Guillain–Barré syndrome. No significant difference between IVIg and PP was found. IVIg should be considered as a treatment option in Guillain–Barré syndrome ( strength of recommendation I ).

Paraproteinemic neuropathy (IgM)

Level of evidence A

There is no reliable evidence to recommend the use of IVIg in paraproteinemic neuropathy. A restricted number of RCT and a systematic review showed only modest benefit with IVIg in the short term ( strength of recommendation IIb ).

Lambert–Eaton myasthenic syndrome

Level of evidence B

A single small RCT showed significant improvement in patients suffering from Lambert–Eaton myasthenic syndrome with the use of IVIg compared to placebo. Therefore, it is acceptable to consider the use of IVIg in this rare and severe neurological syndrome ( strength of recommendation I ).

Stiff-person syndrome

Level of evidence B

Data from a small randomize control trial and several case reports showed that the use of IVIg led to significant improvement in patients with stiff-person syndrome and was superior to placebo. IVIg should be considered as a treatment option in this syndrome especially if the first-line treatment fails ( strength of recommendation I ).

Intractable childhood epilepsy

Level of evidence A

Two RCTs investigated the efficacy of IVIg in patients with intractable childhood epilepsy compared with placebo. Results from these studies do not support benefit from the use of IVIg. Therefore, IVIg is not recommended for the treatment of intractable childhood epilepsy ( strength of recommendation III ).

Critical illness polyneuropathy

Level of evidence C

There is no reliable evidence (level of evidence C-III) to recommend the use of IVIg in the treatment of critical illness polyneuropathy ( strength of recommendation III ).

Rasmussen's encephalitis

Level of evidence C

There is weak evidence indicating significant benefit of IVIg in Rasmussen’s encephalitis either used as monotherapy or combined with other therapies. It should be considered as one of the treatment options in this disease ( strength of recommendation I ).

Myasthenia gravis

Level of evidence A

Several RCTs and a meta-analysis examined the efficacy of IVIg in patient with myasthenia gravis. Results are conflicting. A recent meta-analysis concluded that there is insufficient evidence to determine the efficacy of IVIg in myasthenia gravis. IVIg may be used as treatment for myasthenia gravis severe acute exacerbations ( strength of recommendation IIa ; Table 13 ). Table 13 The use of intravenous immunoglobulins in immunodeficiencies Disease Ref. Study design Intervention including dose and IVIg preparation used Number of patients Results/response X-linked agammaglobulinemia (XLA) [ 403 ] Retrospective trial IVIg was given at doses of >0.25 g/kg every 3 weeks (mean individual residual IgG levels of 700 mg/dl); 24 patients received IVIg from the “Establissements de Transfusion Francais,” others Sandoglobulin (Novartis Institute, Basel) and Endoglobulin (Immuno France, Marseilles) for 3,690 cumulated months 31 patients with XLA at mean age of 24 months followed for a median time of 123 months The incidence of bacterial infections requiring hospitalization fell from 0.4 to 0.06 per patient year ( p < 0.001); the incidence of bacterial infections requiring hospitalization was lower for the periods when patients had residual level of IgG > 800 mg/dl than for the period of levels < 800 mg/dl ( p < 0.001); however, viral or unidentified infections still developed (enteroviral meningitis 3, exudative enteropathy 3, aseptic arthritis 1); at last follow-up, 30 patients were alive at median age of 144 months (range, 58 to 253) [ 404 ] Retrospective trial Patients were treated with different regiments of IVIg between 1965 and 1990; 20 patients were treated before any IVIg was available, 14 patients received IMIg in dose of <0.1 g/kg every 3 weeks; 9 patients were treated at dosages up to 0.2 g/kg every 3 weeks; 15 patients received IVIg at dosages between 0.35 and 0.6 g/kg every 3 weeks (patients receiving different replacement regiments were assigned to more than one group if they received respective regiment for a minimum of 1 year) 29 patients with XLA A significant increase in trough serum IgG ( p = 0.0001) and a significant decrease in the incidence of pneumonias ( p = 0.038) and number of days spent in the hospital in high-dose IVIg group compared with other groups ( p = 0.005); improvement in therapeutic outcome was particularly evident when high-dose IVIg was started before the age of 5; bacterial meningitis, chronic pulmonary disease, and bronchiectasis occurred in IMIg but not in any of IVIg groups [ 405 ] Retrospective trial IVIg 0.3–0.4 g/kg every 3 to 4 weeks 23 patients with XLA treated with IVIg for a mean period of 6.8 ± 4.1 years Significant decrease of the incidence of pneumonia requiring treatment or hospitalization ( p = 0.006) and hospitalizations due to pneumonia ( p = 0.08) [ 406 ] RCT GamaSTAN 20 ml in 2 IM injections every 4 weeks vs. 0.15 g/kg IVIg every 4 weeks (Cutter Laboratories, Inc., Berkeley, CA, USA) during 242 months of treatment 22 patients with antibody deficiency (9 with XLA); 14 (5 with XLA) received IVIg, 13 (7 with XLA) received ISg; 7 patients (3 with XLA) received both ISg and IVIg in separate courses Less acute infections per month of treatment in IVIg group ( p < 0.01; in XLA subgroup, mean 0.8 vs. 2.7); in patients who received separate courses of both IVIg and SIg, infection rate was lower on IVIg ( p < 0.05; in XLA subgroup, mean 0.3 vs. 4.7) [ 407 ] RDB crossover Standard-dose IVIg (adults 300 mg/kg and children 0.4 g/kg every 4 weeks) for 9 months, followed by 3-month washout period and high-dose IVIg (adults 0.6 g/kg and children 0.8 g/kg every 4 weeks) or vice versa (Immunoglobuline IV, Sanquin Blood Supply Foundation, the Netherlands) 41 patients with primary hypogammaglobulinemia (19 patients with XLA) High-dose therapy significantly reduced the number (mean, 3.5 vs. 2.5 per patient ( p = 0.004) and 4.3 vs. 3.4 in XLA subgroup) and duration (median, 33 vs. 21 days ( p = 0.015), in XLA subgroup 28.5 vs. 19 days) of infections Wiscott–Aldrich syndrome (WAS) [ 408 ] Retrospective trial IVIg 0.18–0.58 g/kg every 2–4 weeks and antibiotic prophylaxis with acyclovir and/or fluconazole in some cases 21 patients with WAS Only 4 episodes of sever acute bacterial infection in 451 patient months after splenectomy Hyper-IgE syndrome (Job syndrome) [ 409 ] Case series IVIg 3 adult patients with hyper-IgE syndrome Marked improvement in tendency to infections [ 410 ] Case report Monthly IVIg and interferon gamma three times a week since age 3; he received also prophylaxis with antibiotic and fluconazole 15-year-old boy with hyper-IgE syndrome Good control of disease [ 411 ] Case report IVIg 2 g/kg (Venoglobulin I-Alpha Therapeutic Corporation, Los Angeles, CA, USA) monthly for 7 courses Patient with hyper-IgE syndrome No improvement [ 412 ] Case series IVIg 8 children with recurrent infections, failure to thrive, hypergammaglobulinemia and IgG2 subclass deficiency Clinical resolution [ 413 ] Case series IVIg (Sandoglobulin) 6–12 g monthly 3 members of a family (2 children, 1 adult) with recurrent severe respiratory infections and IgG2 subclass deficiency Clinical resolution IgG subclass deficiencies [ 414 ] Case report IVIg monthly 7 courses A-6-year old child with chronic rhinosinusitis, nasal polyps and IgG3 deficiency Clinical improvement [ 415 ] Case report IVIg monthly A 2-year-old child with recurrent sinopulmonary infections and IgG2 deficiency Clinical improvement [ 416 ] Cases report IVIg 10–15 g every 3 weeks for 6 months 2 patients with treatment-resistant osteomyelitis of the jaw, one with IgG2 deficiency, and the other with IgG3 deficiency Clinical improvement in both patients Specific antibody deficiency [ 417 ] Retrospective study Part of this patients received IVIg 75 patients with recurrent infections and low response to pneumococcal polyvalent vaccine Reduction in number of infections [ 202 ] Series report IVIg 9 children with recurrent sinopulmonary infections and poor response to Haemophilus influenzae type b capsular polysaccharide Reduction of infections upon start of IVIg treatment and recurrence after discontinuation [ 418 ] Case report IVIg Patient with Smith–Lemli–Opitz syndrome, frequent infections and absent response to Pneumovax Same frequency of infections, less severity Hyper-IgM syndrome (HIGM) [ 419 ] Case control study IVIg was administered every 4 weeks and serum IgG levels were consistently maintained above 4 or 5 g/l in most patients 29 patients with HIGM due to activation-induced cytidine deaminase deficiency, suffering from recurrent infections After IVIg therapy was initiated, frequency of infections markedly decreased [ 420 ] Case control IVIg 9 patients with HIGM and recurrent infections Regression in the manifestations of infection [ 421 ] Case control IVIg, 0.25–0.3 g/kg every 4 weeks for 1 year 6 patients with HIGM and recurrent infections Severity and frequency of infections decreased significantly [ 422 ] Case report IVIg with antibiotics, chloroquine, and PD A 6-year-old with HIGM and severe recurrent respiratory infections Mild improvement with a decrease in the inflammatory infiltrate in thoracoscopic biopsy [ 423 ] Case report IVIg and prophylactic antibiotic therapy A 6 years old with CD40 ligand deficiency, chronic neutropenia, and HIGM Management of neutropenia, better quality of life with decreasing occurrence of infection [ 424 ] Case report IVIg A 5-month-old boy with HIGM and severe pneumonia refractory to antibiotics His pneumonia improved; after that, he had no recurrent infections Transient hypogamma of infancy (THI) [ 425 ] Case report IVIg every 4 weeks 1-year-old girl with THI and Staphylococcus aureus sepsis refractory to antibiotics Gradual improvement [ 426 ] Case report Treated with antibiotics and IVIg 1-year-old boy with THI and recurrent sepsis Fewer infections Severe combined immunodeficiency (SCID) [ 427 ] Case control Monthly IVIg 45 children surviving BMT for SCID Effective as adjuvant for BMT Common Variable Immune Deficiency (CVID) [ 428 ] Case series The number of pneumonia episodes was compared prior to and after initiation of IVIg maintenance therapy for 6.6 ± 5.2 years (0.3–0.4 g/kg every 3 to 4 weeks) 50 patients with confirmed CVID Prior to IVIg therapy, 84% of patients had an episode of pneumonia, and 22% had recurrent pneumonias; following IVIg administration, 22% of the patients have acquired pneumonia; this change was found to be statistically significant ( p < 0.001) [ 32 ] Case series Data were collected retrospectively; all the patients were treated by 3 modalities: no IVIg, low-dose IVIg (0.2 g/kg every 3 weeks), and standard-dose IVIg (0.4 g/kg every 3 weeks) 7 patients diagnosed with CVID Number of infections per patient-year was 5 in the no-IVIg period, 2.79 in the low-dose period ( p = 0.002), and 1.53 in the standard-dose period ( p = 0.02); lower respiratory tract infections were markedly decreased due to IVIg therapy [ 31 ] Case series IVIg (Sandoglobulin and/or Nordimmune), 0.4 g/kg every 3 to 4 weeks; the follow-up period was 41.5 ± 35.4 months 26 patients diagnosed with CVID IVIg therapy was associated with significant decrease of annual hospitalization due to pneumonia: from 88.5% to 46% ( p = 0.0025); a significant decrease of total hospital admissions was also observed (from 3.4 to 0.7 per year, p < 0.0005)

X-linked agammaglobulinemia

Level of evidence B

Retrospective analyses revealed that IVIg is beneficial in terms of reduction of acute and chronic infections and days of stay in the hospital. Intravenous route is preferred over intramuscular administration of immunoglobulin and the number and severity of complications are inversely correlated with the dose of IVIg ( strength of recommendation I ).

Wiscott–Aldrich syndrome

Level of evidence C

Despite relatively low evidence of effectiveness of IVIg, the majority of WAS patients are treated with IVIg, which appears to be effective in reduction of acute and chronic infections in these immunodeficient patients ( strength of recommendation IIa ).

Hyper-IgE syndrome (job syndrome)

Level of evidence C

There is weak evidence that IVIg is useful in the treatment of hyper-IgE syndrome. IVIg may be tried in cases in which recurrent live-threatening diseases cannot be controlled by antibiotic prophylaxis ( strength of recommendation IIb ).

IgG subclass deficiencies

Level of evidence C

There is scarce evidence that IVIg is useful in the treatment of IgG subclass deficiencies. Most of the experience reported is patients with IgG2 deficiency. In our opinion, when antibiotic treatment is not effective, IVIg would be a reasonable alternative ( strength of recommendation IIb ).

Specific antibody deficiency

Level of evidence B

This is a heterogeneous group. Specific deficiency of antibodies after vaccination has been found to correlate with infection susceptibility. Most of the published experience regarding IVIg is in patients with deficiency of antibodies to capsular polysaccharide. IVIg has been reported to be beneficial in some cases. This is not surprising as antibodies to bacterial capsular polysaccharide are contained in IVIg [ 30 ]. The evidence for the use of IVIg in specific antibody deficiency is not strong but might be warranted when recurrent infection is present and it is possible to demonstrate low antibody responses to a relevant vaccine ( strength of recommendation IIa ).

Hyper-immunoglobulin-G syndrome

Level of evidence B

The hyper-IgM syndrome (HIGM) is a rare hereditary immune deficiency, characterized by a low or nil level of IgG and IgA and a normal or increased level of IgM, predominately affecting boys. Its clinical manifestations are dominated by recurrent infection, notably of the digestive tube, the ears, nose, and throat and the lungs. IVIg may be considered to treat patients with HIGM and recurrent infections ( strength of recommendation I ).

Transient hypogammaglobulinemia of infancy

Level of evidence C

Transient hypogammaglobulinemia of infancy is characterized by a prolongation and accentuation of the physiologic hypogammaglobulinemia normally occurring during the first 3 to 6 months of life and recovers spontaneously between 18 and 36 months of age. Infants with transient hyogammaglobulinemia of infancy (THI) may remain asymptomatic or develop recurrent sinopulmonary infections, but severe or life-threatening infections are rare. In general, supportive and antimicrobial therapies are sufficient management for the treatment of specific infections in patients with THI. In cases in which infections are severe or refractory to conventional therapy, IVIg is sometimes considered although literature reports are lacking ( strength of recommendation I ).

Severe combined immunodeficiency

Level of evidence B

SCID is a severe form of heritable immunodeficiency in which both “arms” of the adaptive immune system are defected. These babies, if untreated, usually die within 1 year due to severe recurrent infections. Treatment with BMT is successful, and IVIg is used as an adjuvant for this therapy ( strength of recommendation I ).

Common variable immune deficiency

Level of evidence C

Common variable immune deficiency (CVID) is an idiopathic hypoimmunoglobulinemia. World Health Organization diagnostic criteria are well established [ 31 ]. Both B and T cells dysfunction have been observed [ 32 ]. There are both theoretical logic and experimental evidences that support IVIg administration in CVID ( strength of recommendation IIb ).

Primary phagocytic defect

Many different genetic diseases will ultimately result in primary phagocytic defect: cyclic neutropenia, severe congenital neutropenia, Shwachman–Diamond syndrome, leukocyte adhesion deficiency, Rac2 deficiency, interferon-γ and IL-12 defects, chronic granulomatous disease, myeloperoxidase deficiency, Chediak–Higashi syndrome, and neutrophil-specific granule deficiency [ 33 ]. An extensive PubMed-based search revealed little if any information regarding the efficacy of IVIg in the above entities.

IgA deficiency

IgA deficiency may be associated with preventable anaphylaxis or anaphylactoid reaction following IVIg transfusion [ 34 ]. This adverse reaction is encountered in patients with selective IgA deficiency and high titer of anti-IgA antibodies. In those patients, anaphylaxis can be avoided by the use of IgA-depleted IVIg preparation [ 35 ].

Discussion

This article summarizes most of the studies dealing with IVIg administration that were publicized until recently. We have included an array of clinical conditions, some in which the use of IVIg is expected according to their pathogenesis, such as primary immunodeficiencies and rheumatic diseases, and others somewhat less obvious indications including cardiac and oncologic diseases. In some diseases, the usage of IVIg was found to be highly recommended (with a level of evidence A and strength of recommendation I): Kawasaki disease, acquired hypogammaglobulinemia, juvenile rheumatoid arthritis, hemolytic disease of the newborn, acute immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy, and Guillain–Barré syndrome. For many other diseases, treatment with IVIg was found effective as well, but this was less well established, either due to a lack of well-designed studies or due to conflicting evidence among them. In some diseases, there is a strong recommendation against using IVIg (with a level of evidence A and strength of recommendation III): stem cell/bone marrow transplantation, inclusion body myositis, recurrent pregnancy loss due to antiphospholipid syndrome, optic neuritis, and intractable childhood epilepsy. Nevertheless, the effectiveness of IVIg in such a large span of diseases fortifies the accumulating evidence that many pathological conditions are autoimmune mediated.

Abbreviations

year old

intravenous immunoglobulins

randomized controlled trial

interferon

corticosteroids

bone marrow transplantation

hepatitis C virus

prednisone

cyclophosphamide

central nervous system

membranous-proliferative glomerulonephritis

methylprednisolone

plasmapheresis

low-molecular-weight heparin

low-dose aspirin

New York Heart Association

ejection fraction

congestive heart failure

dilated cardiomyopathy

peripartum cardiomyopathy

chronic idiopathic pericarditis

neonatal lupus erythematosus

mucous membrane pemphigoid

expanded disability status scale

very-long-chain fatty acids

glycerol trioleate/erucic supplementation

inflammatory neuropathy cause and treatment disability score

motor conduction velocities

compound muscle action potential

medical research council

relapsing–remitting multiple sclerosis

reference

methotrexate

mycophenolate mofetil

coronary artery aneurysm

References

1. Imbach P Barandun S Baumgartner C Hirt A Hofer F Wagner HP High-dose intravenous gamma globulin therapy of refractory, in particular idiopathic thrombocytopenia in childhood Helv Paediatr Acta 1981 36 81 86 6785258

2. Hunt SA Baker DW Chin MH Cinquegrani MP Feldman AM Francis GS Ganiats TG Goldstein S Gregoratos G Jessup ML Noble RJ Packer M Silver MA Stevenson LW Gibbons RJ Antman EM Alpert JS Faxon DP Fuster V Gregoratos G Jacobs AK Hiratzka LF Russell RO Smith SC Jr ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America Circulation 2001 104 2996 3007 10.1161/hc4901.102568 11739319

3. Katz U Shoenfeld Y Review: intravenous immunoglobulin therapy and thromboembolic complications Lupus 2005 14 802 808 10.1191/0961203303lu2168rr 16302674

4. Orbach H Katz U Sherer Y Shoenfeld Y Intravenous immunoglobulin: adverse effects and safe administration Clin Rev Allergy Immunol 2005 29 173 184 10.1385/CRIAI:29:3:173 16391392

5. Orbach H Tishler M Shoenfeld Y Intravenous immunoglobulin and the kidney—a two-edged sword Semin Arthritis Rheum 2004 34 593 601 10.1016/j.semarthrit.2004.06.003 15609263

6. Federici AB Rand JH Bucciarelli P Budde U van Genderen PJ Mohri H Meyer D Rodeghiero F Sadler JE Acquired von Willebrand syndrome: data from an international registry Thromb Haemost 2000 84 345 349 10959711

7. Federici AB Stabile F Castaman G Canciani MT Mannucci PM Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches Blood 1998 92 2707 2711 9763553

8. Ben-Chetrit E Putterman C Transient neutropenia induced by intravenous immune globulin N Engl J Med 1992 326 270 271 1727981 10.1056/NEJM199201233260413

9. El Alfy MS Mokhtar GM El-Laboudy MA Khalifa AS Randomized trial of anti-D immunoglobulin versus low-dose intravenous immunoglobulin in the treatment of childhood chronic idiopathic thrombocytopenic purpura Acta Haematol 2006 115 46 52 10.1159/000089465 16424649

10. Tarantino MD Young G Bertolone SJ Kalinyak KA Shafer FE Kulkarni R Weber LC Davis ML Lynn H Nugent DJ Single dose of anti-D immune globulin at 75 microg/kg is as effective as intravenous immune globulin at rapidly raising the platelet count in newly diagnosed immune thrombocytopenic purpura in children J Pediatr 2006 148 489 494 10.1016/j.jpeds.2005.11.019 16647411

11. Aukrust P Gullestad L Lappegard KT Ueland T Aass H Wikeby L Simonsen S Froland SS Mollnes TE Complement activation in patients with congestive heart failure: effect of high-dose intravenous immunoglobulin treatment Circulation 2001 104 1494 1500 10.1161/hc3801.096353 11571242

12. McNamara DM Holubkov R Starling RC Dec GW Loh E Torre-Amione G Gass A Janosko K Tokarczyk T Kessler P Mann DL Feldman AM Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy Circulation 2001 103 2254 2259 11342473 10.1161/01.cir.103.18.2254

13. Gullestad L Aass H Fjeld JG Wikeby L Andreassen AK Ihlen H Simonsen S Kjekshus J Nitter-Hauge S Ueland T Lien E Froland SS Aukrust P Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure Circulation 2001 103 220 225 11208680 10.1161/01.cir.103.2.220

14. Kato S Morimoto S Hiramitsu S Uemura A Ohtsuki M Kato Y Miyagishima K Mori N Hishida H Successful high-dose intravenous immunoglobulin therapy for a patient with fulminant myocarditis Heart Vessels 2007 22 48 51 10.1007/s00380-006-0923-3 17285446

15. Stouffer GA Sheahan RG Lenihan DJ Patel P Lenihan DJ The current status of immune modulating therapy for myocarditis: a case of acute parvovirus myocarditis treated with intravenous immunoglobulin Am J Med Sci 2003 326 369 374 10.1097/00000441-200312000-00013 14671501

16. Ozdogu H Boga C Fatal cardiac tamponade in a patient with Kawasaki disease Heart Lung 2005 34 257 259 10.1016/j.hrtlng.2004.12.003 16027646

17. Hunsaker DM Hunsaker JC 3rd Adams KC Noonan JA Ackermann DM Fatal Kawasaki disease due to coronary aneurysm rupture with massive cardiac tamponade J Ky Med Assoc 2003 101 233 238 12838627

18. Soncagi A Devrim I Karagoz T Dilber E Celiker A Ozen S Secmeer G Septated pericarditis associated with Kawasaki disease: a brief case report Turk J Pediatr 2007 49 312 314 17990588

19. Sherer Y Kuechler S Jose Scali J Rovensky J Levy Y Zandman-Goddard G Shoenfeld Y Low dose intravenous immunoglobulin in systemic lupus erythematosus: analysis of 62 cases Isr Med Assoc J 2008 10 55 57 18300575

20. Peterlana D Puccetti A Simeoni S Tinazzi E Corrocher R Lunardi C Efficacy of intravenous immunoglobulin in chronic idiopathic pericarditis: report of four cases Clin Rheumatol 2005 24 18 21 10.1007/s10067-004-0959-7 15674654

21. Shapiro S Shoenfeld Y Gilburd B Sobel E Lahat N Intravenous gamma globulin inhibits the production of matrix metalloproteinase-9 in macrophages Cancer 2002 95 2032 2037 10.1002/cncr.10905 12404299

22. Matsuura E Kobayashi K Inoue K Shoenfeld Y Intravenous immunoglobulin and atherosclerosis Clin Rev Allergy Immunol 2005 29 311 319 10.1385/CRIAI:29:3:311 16391407

23. Williams RV Minich LL Tani LY Pharmacological therapy for patients with Kawasaki disease Paediatr Drugs 2001 3 649 660 10.2165/00128072-200103090-00003 11688596

24. Newburger JW Takahashi M Gerber MA Gewitz MH Tani LY Burns JC Shulman ST Bolger AF Ferrieri P Baltimore RS Wilson WR Baddour LM Levison ME Pallasch TJ Falace DA Taubert KA Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association Pediatrics 2004 114 1708 1733 10.1542/peds.2004-2182 15574639

25. Nussinovitch U Shoenfeld Y Neonatal lupus erythematosus—cardiac manifestations and atrio-ventricular conduction block Harefuah 2007 146 940–944 998 18254446

26. Kaaja R Julkunen H Prevention of recurrence of congenital heart block with intravenous immunoglobulin and corticosteroid therapy: comment on the editorial by Buyon et al Arthritis Rheum 2003 48 280 281 10.1002/art.10716 12528144

27. Letko E Miserocchi E Daoud YJ Christen W Foster CS Ahmed AR A nonrandomized comparison of the clinical outcome of ocular involvement in patients with mucous membrane (cicatricial) pemphigoid between conventional immunosuppressive and intravenous immunoglobulin therapies Clin Immunol 2004 111 303 310 10.1016/j.clim.2003.11.002 15183151

28. Sami N Letko E Androudi S Daoud Y Foster CS Ahmed AR Intravenous immunoglobulin therapy in patients with ocular-cicatricial pemphigoid: a long-term follow-up Ophthalmology 2004 111 1380 1382 10.1016/j.ophtha.2003.11.012 15234140

29. LeHoang P Cassoux N George F Kullmann N Kazatchkine MD Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy Ocul Immunol Inflamm 2000 8 49 57 10806434

30. Hamill RJ Musher DM Groover JE Zavell PJ Watson DA IgG antibody reactive with five serotypes of Streptococcus pneumoniae in commercial intravenous immunoglobulin preparations J Infect Dis 1992 166 38 42 1607706 10.1093/infdis/166.1.38

31. Pourpak Z Aghamohammadi A Sedighipour L Farhoudi A Movahedi M Gharagozlou M Chavoshzadeh Z Jadid L Rezaei N Moin M Effect of regular intravenous immunoglobulin therapy on prevention of pneumonia in patients with common variable immunodeficiency J Microbiol Immunol Infect 2006 39 114 120 16604243

32. Favre O Leimgruber A Nicole A Spertini F Intravenous immunoglobulin replacement prevents severe and lower respiratory tract infections, but not upper respiratory tract and non-respiratory infections in common variable immune deficiency Allergy 2005 60 385 390 10.1111/j.1398-9995.2005.00756.x 15679727

33. Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 2000 343 1703 1714 10.1056/NEJM200012073432307 11106721

34. Katz U Achiron A Sherer Y Shoenfeld Y Safety of intravenous immunoglobulin (IVIG) therapy Autoimmun Rev 2007 6 257 259 10.1016/j.autrev.2006.08.011 17317619

35. Misbah S Intravenous immunoglobulin in the Guillain–Barré syndrome. Products with low IgA content may be used in patients with total IgA deficiency BMJ 1996 313 1400 8956720 10.1136/bmj.313.7069.1400 PMC2352877

36. Levy Y Sherer Y Ahmed A Langevitz P George J Fabbrizzi F Terryberry J Meissner M Lorber M Peter JB Shoenfeld Y A study of 20 SLE patients with intravenous immunoglobulin—clinical and serologic response Lupus 1999 8 705 712 10.1191/096120399678841007 10602441

37. Hundt M Manger K Dorner T Grimbacher B Kalden P Rascu A Weber D Burmester GR Peter HH Kalden JR Schmidt RE Treatment of acute exacerbation of systemic lupus erythematosus with high-dose intravenous immunoglobulin Rheumatology (Oxford) 2000 39 1301 1302 10.1093/rheumatology/39.11.1301 11085821

38. Schroeder JO Zeuner RA Euler HH Loffler H High dose intravenous immunoglobulins in systemic lupus erythematosus: clinical and serological results of a pilot study J Rheumatol 1996 23 71 75 8838511

39. Micheloud D Calderon M Caparrros M D'Cruz DP Intravenous immunoglobulin therapy in severe lupus myocarditis: good outcome in three patients Ann Rheum Dis 2007 66 986 987 10.1136/ard.2006.058784 17576788 PMC1955109

40. Sherer Y Levy Y Shoenfeld Y Marked improvement of severe cardiac dysfunction after one course of intravenous immunoglobulin in a patient with systemic lupus erythematosus Clin Rheumatol 1999 18 238 240 10.1007/s100670050091 11206350

41. Arnal C Piette JC Leone J Taillan B Hachulla E Roudot-Thoraval F Papo T Schaeffer A Bierling P Godeau B Treatment of severe immune thrombocytopenia associated with systemic lupus erythematosus: 59 cases J Rheumatol 2002 29 75 83 11824975

42. Goodfield M Davison K Bowden K Intravenous immunoglobulin (IVIg) for therapy-resistant cutaneous lupus erythematosus (LE) J Dermatolog Treat 2004 15 46 50 10.1080/09546630310018789 14754650

43. De Pita O Bellucci AM Ruffelli M Girardelli CR Puddu P Intravenous immunoglobulin therapy is not able to efficiently control cutaneous manifestations in patients with lupus erythematosus Lupus 1997 6 415 417 10.1177/096120339700600414 9175031

44. Lampropoulos CE Hughes GR DC DP Intravenous immunoglobulin in the treatment of resistant subacute cutaneous lupus erythematosus: a possible alternative Clin Rheumatol 2007 26 981 983 10.1007/s10067-006-0222-5 16670831

45. Genereau T Chosidow O Danel C Cherin P Herson S High-dose intravenous immunoglobulin in cutaneous lupus erythematosus Arch Dermatol 1999 135 1124 1125 10.1001/archderm.135.9.1124 10490126

46. Zandman-Goddard G Levy Y Shoenfeld Y Intravenous immunoglobulin therapy and systemic lupus erythematosus Clin Rev Allergy Immunol 2005 29 219 228 10.1385/CRIAI:29:3:219 16391397

47. Noursadeghi M Aqel N Gibson P Pasvol G Successful treatment of severe Kikuchi's disease with intravenous immunoglobulin Rheumatology (Oxford) 2006 45 235 237 10.1093/rheumatology/kei074 16352644

48. Chen JS Chang KC Cheng CN Tsai WH Su IJ Childhood hemophagocytic syndrome associated with Kikuchi's disease Haematologica 2000 85 998 1000 10980648

49. Vignes S Wechsler B Still's disease in adults: treatment with intravenous immunoglobulins Rev Med Interne 1999 20 Suppl 4 419s 422s 10.1016/S0248-8663(00)88672-5 10522316

50. Permal S Wechsler B Cabane J Perrot S Blum L Imbert JC Treatment of Still disease in adults with intravenous immunoglobulins Rev Med Interne 1995 16 250 254 10.1016/0248-8663(96)80703-X 7746963

51. Liozon E Ly K Aubard Y Vidal E Intravenous immunoglobulins for adult Still's disease and pregnancy Rheumatology (Oxford) 1999 38 1024 1025 10.1093/rheumatology/38.10.1024 10534562

52. Jayne DR Chapel H Adu D Misbah S O'Donoghue D Scott D Lockwood CM Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity QJM 2000 93 433 439 10.1093/qjmed/93.7.433 10874052

53. Jayne DR Lockwood CM Pooled intravenous immunoglobulin in the management of systemic vasculitis Adv Exp Med Biol 1993 336 469 472 8296659 10.1007/978-1-4757-9182-2_84

54. Richter C Schnabel A Csernok E De Groot K Reinhold-Keller E Gross WL Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin Clin Exp Immunol 1995 101 2 7 7621588 10.1111/j.1365-2249.1995.tb02268.x PMC1553313

55. Levy Y Sherer Y George J Langevitz P Ahmed A Bar-Dayan Y Fabbrizzi F Terryberry J Peter J Shoenfeld Y Serologic and clinical response to treatment of systemic vasculitis and associated autoimmune disease with intravenous immunoglobulin Int Arch Allergy Immunol 1999 119 231 238 10.1159/000024199 10436395

56. Jayne DR Lockwood CM Intravenous immunoglobulin as sole therapy for systemic vasculitis Br J Rheumatol 1996 35 1150 1153 10.1093/rheumatology/35.11.1150 8948304

57. Muso E Ito-Ihara T Ono T Imai E Yamagata K Akamatsu A Suzuki K Intravenous immunoglobulin (IVIg) therapy in MPO-ANCA related polyangiitis with rapidly progressive glomerulonephritis in Japan Jpn J Infect Dis 2004 57 S17 S18 15507757

58. Danieli MG Cappelli M Malcangi G Logullo F Salvi A Danieli G Long term effectiveness of intravenous immunoglobulin in Churg–Strauss syndrome Ann Rheum Dis 2004 63 1649 1654 10.1136/ard.2003.015453 15547090 PMC1754837

59. Tsurikisawa N Taniguchi M Saito H Himeno H Ishibashi A Suzuki S Akiyama K Treatment of Churg–Strauss syndrome with high-dose intravenous immunoglobulin Ann Allergy Asthma Immunol 2004 92 80 87 10.1016/S1081-1206(10)61714-0 14756469

60. Carmassi F Morale M Puccetti R Pistelli F Palla R Bevilacqua G Viacava P Antonelli A Mariani G Efficacy of intravenous immunoglobulin therapy in a case of autoimmune-mediated chronic active hepatitis Clin Exp Rheumatol 1992 10 13 17 1551275

61. Malaguarnera M Guccione N Musumeci S Brogna A Motta M Di Fazio I Intravenous immunoglobulin plus interferon-alpha in autoimmune hepatitis C BioDrugs 2004 18 63 70 10.2165/00063030-200418010-00006 14733608

62. Rostoker G Desvaux-Belghiti D Pilatte Y Petit-Phar M Philippon C Deforges L Terzidis H Intrator L Andre C Adnot S Bonin P Bierling P Remy P Lagrue G Lang P Weil B High-dose immunoglobulin therapy for severe IgA nephropathy and Henoch–Schönlein purpura Ann Intern Med 1994 120 476 484 8311370 10.7326/0003-4819-120-6-199403150-00005

63. Lamireau T Rebouissoux L Hehunstre JP Intravenous immunoglobulin therapy for severe digestive manifestations of Henoch–Schönlein purpura Acta Paediatr 2001 90 1081 1082 11683201 10.1111/j.1651-2227.2001.tb01369.x

64. Kusuda A Migita K Tsuboi M Degawa M Matsuoka N Tominaga M Kawakami A Kawabe Y Taguchi T Eguchi K Successful treatment of adult-onset Henoch–Schönlein purpura nephritis with high-dose immunoglobulins Intern Med 1999 38 376 379 10.2169/internalmedicine.38.376 10361914

65. Villarreal IR Ortega O Vigil A Gallar P Oliet A Garcia-Rubiales A Jimenez E Henoch–Schönlein nephritis. Adverse effect of treatment with intravenous immunoglobulin Nephrol Dial Transplant 1999 14 795 797 10.1093/ndt/14.3.795b 10193847

66. Hamidou MA Pottier MA Dupas B Intravenous immunoglobulin in Henoch–Schönlein purpura Ann Intern Med 1996 125 1013 1014 8967701 10.7326/0003-4819-125-12-199612150-00030

67. Matsuda M Miki J Oguchi K Tabata K Ikeda S Fasciitis in mixed connective tissue disease successfully treated with high-dose intravenous immunoglobulin Intern Med 2003 42 910 911 10.2169/internalmedicine.42.910 14518690

68. Ulmer A Kotter I Pfaff A Fierlbeck G Efficacy of pulsed intravenous immunoglobulin therapy in mixed connective tissue disease J Am Acad Dermatol 2002 46 123 127 10.1067/mjd.2001.118539 11756958

69. Levy Y Amital H Langevitz P Nacci F Righi A Conforti L Generini S Matucci Cerinic M Shoenfeld Y Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study Arthritis Rheum 2004 50 1005 1007 10.1002/art.20195 15022346

70. Ihn H Mimura Y Yazawa N Jinnin M Asano Y Yamane K Tamaki K High-dose intravenous immunoglobulin infusion as treatment for diffuse scleroderma Br J Dermatol 2007 156 1058 1060 10.1111/j.1365-2133.2007.07777.x 17381465

71. Nacci F Righi A Conforti ML Miniati I Fiori G Martinovic D Melchiorre D Sapir T Blank M Shoenfeld Y Pignone AM Cerinic MM Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study Ann Rheum Dis 2007 66 977 979 10.1136/ard.2006.060111 17344244 PMC1955090

72. Levy Y Sherer Y Langevitz P Lorber M Rotman P Fabrizzi F Shoenfeld Y Skin score decrease in systemic sclerosis patients treated with intravenous immunoglobulin—a preliminary report Clin Rheumatol 2000 19 207 211 10.1007/s100670050158 10870656

73. Giannini EH Lovell DJ Silverman ED Sundel RP Tague BL Ruperto N Intravenous immunoglobulin in the treatment of polyarticular juvenile rheumatoid arthritis: a phase I/II study. Pediatric Rheumatology Collaborative Study Group J Rheumatol 1996 23 919 924 8724309

74. Oppermann J Mobius D Therapeutical and immunological effects of methylprednisolone pulse therapy in comparison with intravenous immunoglobulin. Treatment in patients with juvenile chronic arthritis Acta Univ Carol Med (Praha) 1994 40 117 121 9355686

75. Uziel Y Laxer RM Schneider R Silverman ED Intravenous immunoglobulin therapy in systemic onset juvenile rheumatoid arthritis: a follow-up study J Rheumatol 1996 23 910 918 8724308

76. Prieur AM Adleff A Debre M Boulate P Griscelli C High dose immunoglobulin therapy in severe juvenile chronic arthritis: long-term follow-up in 16 patients Clin Exp Rheumatol 1990 8 603 608 2289332

77. Kanik KS Yarboro CH Naparstek Y Plotz PH Wilder RL Failure of low-dose intravenous immunoglobulin therapy to suppress disease activity in patients with treatment-refractory rheumatoid arthritis Arthritis Rheum 1996 39 1027 1029 10.1002/art.1780390621 8651966

78. Becker H Mitropoulou G Helmke K Immunomodulating therapy of rheumatoid arthritis by high-dose intravenous immunoglobulin Klin Wochenschr 1989 67 286 290 10.1007/BF01892896 2565412

79. Maksymowych WP Avina-Zubieta A Luong M Russell AS High dose intravenous immunoglobulin (IVIg) in severe refractory rheumatoid arthritis: no evidence for efficacy Clin Exp Rheumatol 1996 14 657 660 8978962

80. Maeda H Furonaka O Matsushima K Awaya Y Kuwabara M Successful treatment of ‘malignant rheumatoid arthritis’ in Japan with pooled intravenous immunoglobulin Rheumatology (Oxford) 2001 40 955 956 10.1093/rheumatology/40.8.955 11511777

81. Takahashi Y Takata T Hoshino M Sakurai M Kanazawa I Benefit of IVIG for long-standing ataxic sensory neuronopathy with Sjögren’s syndrome. IV immunoglobulin Neurology 2003 60 503 505 12578938 10.1212/01.wnl.0000046680.47883.7d

82. Kizawa M Mori K Iijima M Koike H Hattori N Sobue G Intravenous immunoglobulin treatment in painful sensory neuropathy without sensory ataxia associated with Sjögren’s syndrome J Neurol Neurosurg Psychiatry 2006 77 967 969 10.1136/jnnp.2005.084533 16844955 PMC2077613

83. Molina JA Benito-Leon J Bermejo F Jimenez-Jimenez FJ Olivan J Intravenous immunoglobulin therapy in sensory neuropathy associated with Sjögren’s syndrome J Neurol Neurosurg Psychiatry 1996 60 699 10.1136/jnnp.60.6.699 8648349 PMC1073966

84. Dalakas MC Illa I Dambrosia JM Soueidan SA Stein DP Otero C Dinsmore ST McCrosky S A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis N Engl J Med 1993 329 1993 2000 10.1056/NEJM199312303292704 8247075

85. Danieli MG Calcabrini L Marchetti A Calabrese V Pettinari L Massaccesi C Gabrielli A Danieli G Intravenous immunoglobulin treatment in autoimmune diseases Recenti Prog Med 2007 98 322 326 17580523

86. Saito E Koike T Hashimoto H Miyasaka N Ikeda Y Hara M Yamada H Yoshida T Harigai M Ichikawa Y Efficacy of high-dose intravenous immunoglobulin therapy in Japanese patients with steroid-resistant polymyositis and dermatomyositis Mod Rheumatol 2008 18 34 44 10.1007/s10165-007-0013-0 18217197

87. Dalakas MC Koffman B Fujii M Spector S Sivakumar K Cupler E A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM Neurology 2001 56 323 327 11171896 10.1212/wnl.56.3.323

88. Walter MC Lochmuller H Toepfer M Schlotter B Reilich P Schroder M Muller-Felber W Pongratz D High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study J Neurol 2000 247 22 28 10.1007/s004150050005 10701893

89. Dalakas MC Sonies B Dambrosia J Sekul E Cupler E Sivakumar K Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study Neurology 1997 48 712 716 9065553 10.1212/wnl.48.3.712

90. Seider N Beiran I Scharf J Miller B Intravenous immunoglobulin therapy for resistant ocular Behcet's disease Br J Ophthalmol 2001 85 1287 1288 10.1136/bjo.85.11.1287 11673289 PMC1723778

91. Rewald E Jaksic JC Behcet's syndrome treated with high-dose intravenous IgG and low-dose aspirin J R Soc Med 1990 83 652 653 2286970 10.1177/014107689008301021 PMC1292866

92. Schwartz RS Gabriel DA Aledort LM Green D Kessler CM A prospective study of treatment of acquired (autoimmune) factor VIII inhibitors with high-dose intravenous gamma globulin Blood 1995 86 797 804 7606010

93. Crenier L Ducobu J des Grottes JM Cerny J Delaunoit C Capel P Low response to high-dose intravenous immunoglobulin in the treatment of acquired factor VIII inhibitor Br J Haematol 1996 95 750 753 10.1046/j.1365-2141.1996.d01-1965.x 8982056

94. Yamamoto K Takamatsu J Saito H Intravenous immunoglobulin therapy for acquired coagulation inhibitors: a critical review Int J Hematol 2007 85 287 293 10.1532/IJH97.06222 17483070

95. Dykes AC Walker ID Lowe GD Tait RC Combined prednisolone and intravenous immunoglobulin treatment for acquired factor VIII inhibitors: a 2-year review Haemophilia 2001 7 160 163 10.1046/j.1365-2516.2001.00489.x 11260275

96. Molica S Musto P Chiurazzi F Specchia G Brugiatelli M Cicoira L Levato D Nobile F Carotenuto M Liso V Rotoli B Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study Haematologica 1996 81 121 126 8641639

97. Griffiths H Brennan V Lea J Bunch C Lee M Chapel H Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors Blood 1989 73 366 368 2492832

98. Boughton BJ Jackson N Lim S Smith N Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia Clin Lab Haematol 1995 17 75 80 7621634 10.1111/j.1365-2257.1995.tb00322.x

99. Chapel HM Lee M Hargreaves R Pamphilon DH Prentice AG Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma Lancet 1994 343 1059 1063 10.1016/S0140-6736(94)90180-5 7909099

100. Gimesi A Eibl M Koos R Somlo P Magyarossy E Kardos G Fazekas E Schmidt M Borsi J Schuler D Immunoglobulin prophylaxis during intensive treatment of acute lymphoblastic leukemia in children Acta Paediatr Hung 1992 32 115 125 1389316

101. Sumer T Abumelha A al-Mulhim I al-Fadil M Treatment of fever and neutropenia with antibiotics versus antibiotics plus intravenous gamma globulin in childhood leukemia Eur J Pediatr 1989 148 401 402 10.1007/BF00595896 2493376

102. Bunch C Immunoglobulin replacement in chronic lymphocytic leukaemia Nouv Rev Fr Hematol 1988 30 419 422 3065737

103. Musto P Brugiatelli M Carotenuto M Prophylaxis against infections with intravenous immunoglobulins in multiple myeloma Br J Haematol 1995 89 945 946 7772543 10.1111/j.1365-2141.1995.tb08447.x

104. Chapel H Griffiths H Brennan V Bunch C Lea J Lee M Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy Immunol Invest 1991 20 187 191 10.3109/08820139109050786 1864637

105. Ballester OF Saba HI Moscinski LC Nelson R Foulis P Pure red cell aplasia: treatment with intravenous immunoglobulin concentrate Semin Hematol 1992 29 106 108 1509289

106. Clauvel JP Vainchenker W Herrera A Dellagi K Vinci G Tabilio A Lacombe C Treatment of pure red cell aplasia by high dose intravenous immunoglobulins Br J Haematol 1983 55 380 382 10.1111/j.1365-2141.1983.tb01260.x 6615731

107. Tang JW Lau JS Wong SY Cheung JL Chan CH Wong KF Wong A Chan PK Dose-by-dose virological and hematological responses to intravenous immunoglobulin in an immunocompromised patient with persistent parvovirus B19 infection J Med Virol 2007 79 1401 1405 10.1002/jmv.20870 17607784

108. Liang TB Li DL Yu J Bai XL Liang L Xu SG Wang WL Shen Y Zhang M Zheng SS Pure red cell aplasia due to parvovirus B19 infection after liver transplantation: a case report and review of the literature World J Gastroenterol 2007 13 2007 2010 17461508 10.3748/wjg.v13.i13.2007 PMC4146984

109. Subtirelu MM Flynn JT Schechner RS Pullman JM Feuerstein D Del Rio M Acute renal failure in a pediatric kidney allograft recipient treated with intravenous immunoglobulin for parvovirus B19 induced pure red cell aplasia Pediatr Transplant 2005 9 801 804 10.1111/j.1399-3046.2005.00379.x 16269055

110. Song KW Mollee P Patterson B Brien W Crump M Pure red cell aplasia due to parvovirus following treatment with CHOP and rituximab for B-cell lymphoma Br J Haematol 2002 119 125 127 10.1046/j.1365-2141.2002.03778.x 12358915

111. Castelli R Vismara A Pavia G Dagani R Porro T Relapsing pure red cell aplasia associated with B-cell chronic lymphocytic leukemia successfully treated by intravenous immunoglobulin concentrate Ann Ital Med Int 2002 17 47 50 11975114

112. Choi SH Chang SP Won JC Lee JS Chi HS Yang WS Park SK A case of persistent anemia in a renal transplant recipient: association with parvovirus B19 infection Scand J Infect Dis 2002 34 71 75 10.1080/003655402753395247 11874173

113. Borkowski J Amrikachi M Hudnall SD Fulminant parvovirus infection following erythropoietin treatment in a patient with acquired immunodeficiency syndrome Arch Pathol Lab Med 2000 124 441 445 10705404 10.5858/2000-124-0441-FPIFET

114. Koduri PR Kumapley R Valladares J Teter C Chronic pure red cell aplasia caused by parvovirus B19 in AIDS: use of intravenous immunoglobulin—a report of eight patients Am J Hematol 1999 61 16 20 10.1002/(SICI)1096-8652(199905)61:1<16::AID-AJH4>3.0.CO;2-Y 10331506

115. Chuhjo T Nakao S Matsuda T Successful treatment of persistent erythroid aplasia caused by parvovirus B19 infection in a patient with common variable immunodeficiency with low-dose immunoglobulin Am J Hematol 1999 60 222 224 10.1002/(SICI)1096-8652(199903)60:3<222::AID-AJH9>3.0.CO;2-K 10072114

116. Koduri PR Kumapley R Khokha ND Patel AR Red cell aplasia caused by parvovirus B19 in AIDS: use of i.v. immunoglobulin Ann Hematol 1997 75 67 68 10.1007/s002770050315 9322687

117. Fuller A Moaven L Spelman D Spicer WJ Wraight H Curtis D Leydon J Doultree J Locarnini S Parvovirus B19 in HIV infection: a treatable cause of anemia Pathology 1996 28 277 280 10.1080/00313029600169154 8912362

118. Ramratnam B Gollerkeri A Schiffman FJ Rintels P Flanigan TP Management of persistent B19 parvovirus infection in AIDS Br J Haematol 1995 91 90 92 10.1111/j.1365-2141.1995.tb05250.x 7577659

119. Mant MJ Chronic idiopathic pure red cell aplasia: successful treatment during pregnancy and durable response to intravenous immunoglobulin J Intern Med 1994 236 593 595 10.1111/j.1365-2796.1994.tb00851.x 7964439

120. Ilan Y Naparstek Y Pure red cell aplasia associated with systemic lupus erythematosus: remission after a single course of intravenous immunoglobulin Acta Haematol 1993 89 152 154 10.1159/000204509 8362604

121. Ramage JK Hale A Gane E Cohen B Boyle M Mufti G Williams R Parvovirus B19-induced red cell aplasia treated with plasmapheresis and immunoglobulin Lancet 1994 343 667 668 10.1016/S0140-6736(94)92659-X 7906821

122. McGuire WA Yang HH Bruno E Brandt J Briddell R Coates TD Hoffman R Treatment of antibody-mediated pure red-cell aplasia with high-dose intravenous gamma globulin N Engl J Med 1987 317 1004 1008 3116428 10.1056/NEJM198710153171606

123. Karmochkine M Oksenhendler E Leruez-Ville M Jaccard A Morinet F Herson S Persistent parvovirus B19 infection and pure red cell aplasia in Waldenstrom's macroglobulinemia: successful treatment with high-dose intravenous immunoglobulin Am J Hematol 1995 50 227 228 10.1002/ajh.2830500319 7485092

124. Mohri H Motomura S Kanamori H Matsuzaki M Watanabe S Maruta A Kodama F Okubo T Clinical significance of inhibitors in acquired von Willebrand syndrome Blood 1998 91 3623 3629 9572997

125. Viallard JF Pellegrin JL Vergnes C Borel-Derlon A Clofent-Sanchez G Nurden AT Leng B Nurden P Three cases of acquired von Willebrand disease associated with systemic lupus erythematosus Br J Haematol 1999 105 532 537 10.1111/j.1365-2141.1999.01360.x 10233433

126. Sadowitz PD Dubowy RL Intravenous immunoglobulin in the treatment of aplastic anemia Am J Pediatr Hematol Oncol 1990 12 198 200 10.1097/00043426-199022000-00014 2378414

127. Bergen GA Sakalosky PE Sinnott JT Transient aplastic anemia caused by parvovirus B19 infection in a heart transplant recipient J Heart Lung Transplant 1996 15 843 845 8878766

128. Sherer Y Levy Y Fabbrizzi F Shoenfeld Y Treatment of hematologic disorders other than immune thrombocytopenic purpura with intravenous immunoglobulin (IVIg)—report of seven cases and review of the literature Eur J Intern Med 2000 11 85 88 10.1016/S0953-6205(00)00067-4 10745151

129. Flores G Cunningham-Rundles C Newland AC Bussel JB Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients Am J Hematol 1993 44 237 242 10.1002/ajh.2830440404 8237993

130. Bux J Behrens G Jaeger G Welte K Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases Blood 1998 91 181 186 9414283

131. Hilgartner MW Bussel J Use of intravenous gamma globulin for the treatment of autoimmune neutropenia of childhood and autoimmune hemolytic anemia Am J Med 1987 83 25 29 10.1016/0002-9343(87)90547-X 3118705

132. Mathew P Chen G Wang W Evans syndrome: results of a national survey J Pediatr Hematol Oncol 1997 19 433 437 10.1097/00043426-199709000-00005 9329465

133. Scaradavou A Bussel J Evans syndrome. Results of a pilot study utilizing a multiagent treatment protocol J Pediatr Hematol Oncol 1995 17 290 295 10.1097/00043426-199511000-00003 7583383

134. Nuss R Wang W Intravenous gamma globulin for thrombocytopenia in children with Evans syndrome Am J Pediatr Hematol Oncol 1987 9 164 167 10.1097/00043426-198722000-00012 2438958

135. Chang DK Yoo DH Kim TH Jun JB Lee IH Bae SC Kim IS Kim SY Induction of remission with intravenous immunoglobulin and cyclophosphamide in steroid-resistant Evans' syndrome associated with dermatomyositis Clin Rheumatol 2001 20 63 66 10.1007/s100670170107 11254245

136. Kaplan C Murphy MF Kroll H Waters AH Feto-maternal alloimmune thrombocytopenia: antenatal therapy with IvIgG and steroids—more questions than answers. European Working Group on FMAIT Br J Haematol 1998 100 62 65 10.1046/j.1365-2141.1998.00533.x 9450792

137. Cordonnier C Chevret S Legrand M Rafi H Dhedin N Lehmann B Bassompierre F Gluckman E Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled, multicenter trial Ann Intern Med 2003 139 8 18 12834313 10.7326/0003-4819-139-1-200307010-00007

138. Zikos P Van Lint MT Lamparelli T Gualandi F Occhini D Mordini N Berisso G Bregante S Bacigalupo A A randomized trial of high dose polyvalent intravenous immunoglobulin (HDIgG) vs. cytomegalovirus (CMV) hyperimmune IgG in allogeneic hemopoietic stem cell transplants (HSCT) Haematologica 1998 83 132 137 9549924

139. Sullivan KM Storek J Kopecky KJ Jocom J Longton G Flowers M Siadak M Nims J Witherspoon RP Anasetti C Appelbaum FR Bowden RA Buckner CD Crawford SW Deeg HJ Hansen JA McDonald GB Sanders JE Storb R A controlled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic graft-vs.-host disease after marrow transplantation: clinical outcome and effect on subsequent immune recovery Biol Blood Marrow Transplant 1996 2 44 53 9078354

140. Winston DJ Ho WG Bartoni K Champlin RE Intravenous immunoglobulin and CMV-seronegative blood products for prevention of CMV infection and disease in bone marrow transplant recipients Bone Marrow Transplant 1993 12 283 288 8241988

141. Winston DJ Antin JH Wolff SN Bierer BE Small T Miller KB Linker C Kaizer H Lazarus HM Petersen FB Cowan MJ Ho WG Wingard JR Schiller GJ Territo MC Jiao J Petrarca MA Tonetta SA A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation Bone Marrow Transplant 2001 28 187 196 10.1038/sj.bmt.1703109 11509937

142. Wolff SN Fay JW Herzig RH Greer JP Dummer S Brown RA Collins RH Stevens DA Herzig GP High-dose weekly intravenous immunoglobulin to prevent infections in patients undergoing autologous bone marrow transplantation or severe myelosuppressive therapy. A study of the American Bone Marrow Transplant Group Ann Intern Med 1993 118 937 942 8489107 10.7326/0003-4819-118-12-199306150-00004

143. Sullivan KM Kopecky KJ Jocom J Fisher L Buckner CD Meyers JD Counts GW Bowden RA Peterson FB Witherspoon RP Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation N Engl J Med 1990 323 705 712 2167452 10.1056/NEJM199009133231103

144. Alcock GS Liley H Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates Cochrane Database Syst Rev 2002 3 CD003313 12137687 10.1002/14651858.CD003313

145. Gottstein R Cooke RW Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn Arch Dis Child Fetal Neonatal Ed 2003 88 F6 F10 10.1136/fn.88.1.F6 12496219 PMC1755998

146. Kohan AI Niborski RC Rey JA Amerise G Vazquez MI Zani N Calahonra R Binaghi A Sanchez Avalos J High-dose intravenous immunoglobulin in non-ABO transfusion incompatibility Vox Sang 1994 67 195 198 10.1111/j.1423-0410.1994.tb01659.x 7801611

147. Woodcock BE Walker S Adams K Haemolytic transfusion reaction—successful attenuation with methylprednisolone and high dose immunoglobulin Clin Lab Haematol 1993 15 59 61 10.1111/j.1365-2257.1993.tb00122.x 8472498

148. Win N Doughty H Telfer P Wild BJ Pearson TC Hyperhemolytic transfusion reaction in sickle cell disease Transfusion 2001 41 323 328 10.1046/j.1537-2995.2001.41030323.x 11274584

149. Win N Yeghen T Needs M Chen FE Okpala I Use of intravenous immunoglobulin and intravenous methylprednisolone in hyperhaemolysis syndrome in sickle cell disease Hematology 2004 9 433 436 10.1080/10245330400001926 15763986

150. Cullis JO Win N Dudley JM Kaye T Post-transfusion hyperhaemolysis in a patient with sickle cell disease: use of steroids and intravenous immunoglobulin to prevent further red cell destruction Vox Sang 1995 69 355 357 10.1111/j.1423-0410.1995.tb00373.x 8751307

151. Robson WL Fick GH Jadavji T Leung AK The use of intravenous gamma globulin in the treatment of typical hemolytic uremic syndrome Pediatr Nephrol 1991 5 289 292 10.1007/BF00867478 1714289

152. Sheth KJ Gill JC Leichter HE High-dose intravenous gamma globulin infusions in hemolytic–uremic syndrome: a preliminary report Am J Dis Child 1990 144 268 270 1689539 10.1001/archpedi.1990.02150270014009

153. Centurioni R Bobbio-Pallavicini E Porta C Rodeghiero F Gugliotta L Billio A Tacconi F Ascari E Treatment of thrombotic thrombocytopenic purpura with high-dose immunoglobulins. Results in 17 patients. Italian Cooperative Group for TTP Haematologica 1995 80 325 331 7590501

154. Dervenoulas J Tsirigotis P Bollas G Koumarianou AA Pappa V Mantzios G Xiros N Economopoulos T Papageorgiou E Pappa M Raptis SA Efficacy of intravenous immunoglobulin in the treatment of thrombotic thrombocytopaenic purpura. A study of 44 cases Acta Haematol 2001 105 204 208 10.1159/000046567 11528094

155. Winder A Shoenfeld Y Hochman R Keren G Levy Y Eldor A High-dose intravenous gamma-globulins for heparin-induced thrombocytopenia: a prompt response J Clin Immunol 1998 18 330 334 10.1023/A:1023238915316 9793825

156. Prull A Nechwatal R Riedel H Maurer W The therapy of the heparin-induced thrombosis–thrombocytopenia syndrome with immunoglobulins Dtsch Med Wochenschr 1992 117 1838 1842 10.1055/s-2008-1062518 1451649

157. Jahnke L Applebaum S Sherman LA Greenberger PA Green D An evaluation of intravenous immunoglobulin in the treatment of human immunodeficiency virus-associated thrombocytopenia Transfusion 1994 34 759 764 10.1046/j.1537-2995.1994.34994378275.x 8091463

158. Godeau B Chevret S Varet B Lefrere F Zini JM Bassompierre F Cheze S Legouffe E Hulin C Grange MJ Fain O Bierling P Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial Lancet 2002 359 23 29 10.1016/S0140-6736(02)07275-6 11809183

159. Jacobs P Wood L The comparison of gamma globulin to steroids in treating adult immune thrombocytopenia. An interim analysis Blut 1989 59 92 95 10.1007/BF00320256 2752179

160. Blanchette VS Luke B Andrew M Sommerville-Nielsen S Barnard D de Veber B Gent M A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura J Pediatr 1993 123 989 995 10.1016/S0022-3476(05)80400-7 8229536

161. Duru F Fisgin T Yarali N Kara A Clinical course of children with immune thrombocytopenic purpura treated with intravenous immunoglobulin G or megadose methylprednisolone or observed without therapy Pediatr Hematol Oncol 2002 19 219 225 10.1080/08880010252899370 12051587

162. Rarick MU Montgomery T Groshen S Sullivan-Halley J Jamin D Mazumder A Gill PS Loureiro C Levine AM Intravenous immunoglobulin in the treatment of human immunodeficiency virus-related thrombocytopenia Am J Hematol 1991 38 261 266 10.1002/ajh.2830380402 1746533

163. Majluf-Cruz A Luna-Castanos G Huitron S Nieto-Cisneros L Usefulness of a low-dose intravenous immunoglobulin regimen for the treatment of thrombocytopenia associated with AIDS Am J Hematol 1998 59 127 132 10.1002/(SICI)1096-8652(199810)59:2<127::AID-AJH5>3.0.CO;2-# 9766797

164. Colovic M Dimitrijevic M Sonnenburg C Suvajdzic N Donfrid M Bogdanovic A Clinical efficacy and safety of a novel intravenous immunoglobulin preparation in adult chronic ITP Hematol J 2003 4 358 362 10.1038/sj.thj.6200303 14502262

165. Godeau B Lesage S Divine M Wirquin V Farcet JP Bierling P Treatment of adult chronic autoimmune thrombocytopenic purpura with repeated high-dose intravenous immunoglobulin Blood 1993 82 1415 1421 8364194

166. Mueller-Eckhardt C Kuenzlen E Thilo-Korner D Pralle H High-dose intravenous immunoglobulin for post-transfusion purpura N Engl J Med 1983 308 287 6681546 10.1056/NEJM198302033080526

167. Becker T Panzer S Maas D Kiefel V Sprenger R Kirschbaum M Mueller-Eckhardt C High-dose intravenous immunoglobulin for post-transfusion purpura Br J Haematol 1985 61 149 155 10.1111/j.1365-2141.1985.tb04071.x 4052323

168. Walker WS Yap PL Kilpatrick DC Boulton FE Crawford RJ Sang CT Post-transfusion purpura following open heart surgery: management by high dose intravenous immunoglobulin infusion Ann Hematol 1988 57 323 325 10.1007/BF00320364 3196884

169. Asci G Toz H Ozkahya M Cagirgan S Duman S Sezis S Ok E High-dose immunoglobulin therapy in renal transplant recipients with hemophagocytic histiocytic syndrome J Nephrol 2006 19 322 326 16874692

170. Chen CJ Huang YC Jaing TH Hung IJ Yang CP Chang LY Lin TY Hemophagocytic syndrome: a review of 18 pediatric cases J Microbiol Immunol Infect 2004 37 157 163 15221035

171. Chen RL Lin KH Lin DT Su IJ Huang LM Lee PI Hseih KH Lin KS Lee CY Immunomodulation treatment for childhood virus-associated haemophagocytic lymphohistiocytosis Br J Haematol 1995 89 282 290 10.1111/j.1365-2141.1995.tb03302.x 7873378

172. Ningsanond V Infection associated hemophagocytic syndrome: a report of 50 children J Med Assoc Thai 2000 83 1141 1149 11143479

173. Freeman B Rathore MH Salman E Joyce MJ Pitel P Intravenously administered immune globulin for the treatment of infection-associated hemophagocytic syndrome J Pediatr 1993 123 479 481 10.1016/S0022-3476(05)81761-5 8155113

174. Hot A Madoux MH Viard JP Coppere B Ninet J Successful treatment of cytomegalovirus-associated hemophagocytic syndrome by intravenous immunoglobulins Am J Hematol 2008 83 159 162 10.1002/ajh.21008 17849465

175. Benito-Leon J Lopez-Rios F Rodriguez-Martin FJ Madero S Ruiz J Rapidly deteriorating polyneuropathy associated with osteosclerotic myeloma responsive to intravenous immunoglobulin and radiotherapy J Neurol Sci 1998 158 113 117 10.1016/S0022-510X(98)00107-5 9667789

176. Huang CC Chu CC Poor response to intravenous immunoglobulin therapy in patients with Castleman's disease and the POEMS syndrome J Neurol 1996 243 726 727 10.1007/BF00873980 8923307

177. Chang YJ Huang CC Chu CC Intravenous immunoglobulin therapy in POEMS syndrome: a case report Zhonghua Yi Xue Za Zhi (Taipei) 1996 58 366 369 9037854

178. Cantarovich M Barkun JS Forbes RD Kosiuk JP Tchervenkov JI Successful treatment of post-transplant lymphoproliferative disorder with interferon-alpha and intravenous immunoglobulin Clin Transplant 1998 12 109 115 9575398

179. Leroy F Sechet A Abou Ayache R Thierry A Belmouaz S Desport E Bauwens M Bridoux F Touchard G Cytomegalovirus prophylaxis with intravenous polyvalent immunoglobulin in high-risk renal transplant recipients Transplant Proc 2006 38 2324 2326 10.1016/j.transproceed.2006.07.001 16980080

180. The National Institute of Child Health and Human Developments Intravenous Immunoglobulin Study Group Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection N Engl J Med 1991 325 73 80 10.1056/NEJM199107113250201 1675763

181. Olopoenia L Young M White D Barnes S Rahbar F Fomufod A Intravenous immunoglobulin in symptomatic and asymptomatic children with perinatal HIV infection J Natl Med Assoc 1997 89 543 547 9264222 PMC2568113

182. Goldring JD Molyneux ME Taylor T Wirima J Hommel M Plasmodium falciparum : diversity of isolates from Malawi in their cytoadherence to melanoma cells and monocytes in vitro Br J Haematol 1992 81 413 418 10.1111/j.1365-2141.1992.tb08249.x 1390216

183. Sabchareon A Burnouf T Ouattara D Attanath P Bouharoun-Tayoun H Chantavanich P Foucault C Chongsuphajaisiddhi T Druilhe P Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria Am J Trop Med Hyg 1991 45 297 308 1928564 10.4269/ajtmh.1991.45.297

184. Gonzalez H Sunnerhagen KS Sjoberg I Kaponides G Olsson T Borg K Intravenous immunoglobulin for post-polio syndrome: a randomised controlled trial Lancet Neurol 2006 5 493 500 10.1016/S1474-4422(06)70447-1 16713921

185. Farbu E Rekand T Vik-Mo E Lygren H Gilhus NE Aarli JA Post-polio syndrome patients treated with intravenous immunoglobulin: a double-blinded randomized controlled pilot study Eur J Neurol 2007 14 60 65 10.1111/j.1468-1331.2006.01552.x 17222115

186. Kaponides G Gonzalez H Olsson T Borg K Effect of intravenous immunoglobulin in patients with post-polio syndrome—an uncontrolled pilot study J Rehabil Med 2006 38 138 140 10.1080/16501970500441625 16546773

187. Laupland KB Kirkpatrick AW Delaney A Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis Crit Care Med 2007 35 2686 2692 10.1097/01.CCM.0000295312.13466.1C 18074465

188. Hamdan A Green P Mendelson E Kramer MR Pitlik S Weinberger M Possible benefit of intravenous immunoglobulin therapy in a lung transplant recipient with West Nile virus encephalitis Transpl Infect Dis 2002 4 160 162 10.1034/j.1399-3062.2002.01014.x 12421462

189. Shimoni Z Niven MJ Pitlick S Bulvik S Treatment of West Nile virus encephalitis with intravenous immunoglobulin Emerg Infect Dis 2001 7 759 10.3201/eid0704.010432 11585547 PMC2631768

190. The Intravenous Immunoglobulin Collaborative Study Group Prophylactic intravenous administration of standard immune globulin as compared with core-lipopolysaccharide immune globulin in patients at high risk of postsurgical infection N Engl J Med 1992 327 234 240 1614464 10.1056/NEJM199207233270404

191. Glinz W Grob PJ Nydegger UE Ricklin T Stamm F Stoffel D Lasance A Polyvalent immunoglobulins for prophylaxis of bacterial infections in patients following multiple trauma. A randomized, placebo-controlled study Intensive Care Med 1985 11 288 294 10.1007/BF00273538 3936866

192. Munster AM Moran KT Thupari J Allo M Winchurch RA Prophylactic intravenous immunoglobulin replacement in high-risk burn patients J Burn Care Rehabil 1987 8 376 380 10.1097/00004630-198709000-00007 2822723

193. Gooding AM Bastian JF Peterson BM Wilson NW Safety and efficacy of intravenous immunoglobulin prophylaxis in pediatric head trauma patients: a double-blind controlled trial J Crit Care 1993 8 212 216 10.1016/0883-9441(93)90004-5 8305958

194. Douzinas EE Pitaridis MT Louris G Andrianakis I Katsouyanni K Karmpaliotis D Economidou J Syfras D Roussos C Prevention of infection in multiple trauma patients by high-dose intravenous immunoglobulins Crit Care Med 2000 28 8 15 10.1097/00003246-200001000-00002 10667492

195. Kress HG Scheidewig C Schmidt H Silber R Reduced incidence of postoperative infection after intravenous administration of an immunoglobulin A- and immunoglobulin M-enriched preparation in anergic patients undergoing cardiac surgery Crit Care Med 1999 27 1281 1287 10.1097/00003246-199907000-00011 10446821

196. Chapel H Dicato M Gamm H Brennan V Ries F Bunch C Lee M Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes Br J Haematol 1994 88 209 212 10.1111/j.1365-2141.1994.tb05002.x 7803248

197. Haywood CT McGeer A Low DE Clinical experience with 20 cases of group A streptococcus necrotizing fasciitis and myonecrosis: 1995 to 1997 Plast Reconstr Surg 1999 103 1567 1573 10.1097/00006534-199905060-00003 10323689

198. Norrby-Teglund A Muller MP McGeer A Gan BS Guru V Bohnen J Thulin P Low DE Successful management of severe group A streptococcal soft tissue infections using an aggressive medical regimen including intravenous polyspecific immunoglobulin together with a conservative surgical approach Scand J Infect Dis 2005 37 166 172 15849047 10.1080/00365540410020866

199. Arnholm B Lundqvist A Stromberg A High-dose immunoglobulin—life-saving in invasive group A streptococcal infection. Report of eleven cases with only one fatality Lakartidningen 2004 101 2642 2644 15458217

200. Korzets A Ori Y Zevin D Weinberger M Kesslin J Seror D Kuperman A Gafter U Group A streptococcal bacteraemia and necrotizing fasciitis in a renal transplant patient: a case for intravenous immunoglobulin therapy Nephrol Dial Transplant 2002 17 150 152 10.1093/ndt/17.1.150 11773482

201. Kalm O Prellner K Christensen P The effect of intravenous immunoglobulin treatment in recurrent acute otitis media Int J Pediatr Otorhinolaryngol 1986 11 237 246 10.1016/S0165-5876(86)80035-0 3533818

202. Silk HJ Ambrosino D Geha RS Effect of intravenous gamma globulin therapy in IgG2 deficient and IgG2 sufficient children with recurrent infections and poor response to immunization with Haemophilus influenzae type b capsular polysaccharide antigen Ann Allergy 1990 64 21 25 2297141

203. Huang YC Lin TY Lin YJ Lien RI Chou YH Prophylaxis of intravenous immunoglobulin and acyclovir in perinatal varicella Eur J Pediatr 2001 160 91 94 10.1007/s004310000640 11271397

204. Lin SJ Lin TY Chiu CH Huang YC Experience of intravenous immunoglobulin and acyclovir in neonates at risk for severe varicella infection—report of five cases Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1995 36 53 57 7778448

205. Saitou M Niitsuma K Kasukawa R Two cases of severe adult varicella pneumonia Nihon Kokyuki Gakkai Zasshi 1998 36 251 255 9656672

206. Shirai T Sano K Matsuyama S Honjo Y Takashima M Sasada Y Takayanagi S Nagamatsu K Nawano M Fushimi M Imokawa S Sato A Varicella pneumonia in a healthy adult presenting with severe respiratory failure Intern Med 1996 35 315 318 10.2169/internalmedicine.35.315 8739789

207. Tokat O Kelebek N Turker G Kahveci SF Ozcan B Intravenous immunoglobulin in adult varicella pneumonia complicated by acute respiratory distress syndrome J Int Med Res 2001 29 252 255 11471863 10.1177/147323000102900313

208. Chou DW Lee CH Chen CW Chang HY Hsiue TR Varicella pneumonia complicated by acute respiratory distress syndrome in an adult J Formos Med Assoc 1999 98 778 782 10705696

209. Hara T Mizuno Y Igarashi H Ueda K Intravenous gamma globulin therapy for thrombocytopenic purpura associated with active varicella infection Eur J Pediatr 1987 146 531 532 10.1007/BF00441611 3678280

210. Kaneda K Kojima K Shinagawa K Ishimaru F Ikeda K Niiya K Harada M An adult patient with varicella preceded by acute thrombocytopenia Rinsho Ketsueki 2001 42 1142 1144 11808086

211. Whitington PF Hibbard JU High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis Lancet 2004 364 1690 1698 10.1016/S0140-6736(04)17356-X 15530630

212. Hutton B Sharma R Fergusson D Tinmouth A Hebert P Jamieson J Walker M Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review BJOG 2007 114 134 142 10.1111/j.1471-0528.2006.01201.x 17166218

213. Porter TF LaCoursiere Y Scott JR Immunotherapy for recurrent miscarriage Cochrane Database Syst Rev 2006 4 CD000112 10.1002/14651858.CD000112.pub2 16625529

214. The Practice Committee of the American Society for Reproductive Medicine Intravenous immunoglobulin (IVIG) and recurrent spontaneous pregnancy loss Fertil Steril 2006 86 S226 S227 17055829 10.1016/j.fertnstert.2006.08.047

215. Christiansen OB Pedersen B Rosgaard A Husth M A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage Hum Reprod 2002 17 809 816 10.1093/humrep/17.3.809 11870141

216. Daya S Gunby J Porter F Scott J Clark DA Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage Hum Reprod Update 1999 5 475 482 10.1093/humupd/5.5.475 10582784

217. Perino A Vassiliadis A Vucetich A Colacurci N Menato G Cignitti M Semprini AE Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study Hum Reprod 1997 12 2388 2392 10.1093/humrep/12.11.2388 9436670

218. Coulam CB Krysa L Stern JJ Bustillo M Intravenous immunoglobulin for treatment of recurrent pregnancy loss Am J Reprod Immunol 1995 34 333 337 8607936 10.1111/j.1600-0897.1995.tb00960.x

219. Christiansen OB Mathiesen O Husth M Rasmussen KL Ingerslev HJ Lauritsen JG Grunnet N Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin Hum Reprod 1995 10 2690 2695 8567794 10.1093/oxfordjournals.humrep.a135769

220. The German RSA/IVIG Group Intravenous immunoglobulin in the prevention of recurrent miscarriage Br J Obstet Gynaecol 1994 101 1072 1077 7826961 10.1111/j.1471-0528.1994.tb13584.x

221. Empson M Lassere M Craig J Scott J Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant Cochrane Database Syst Rev 2005 2 CD002859 15846641 10.1002/14651858.CD002859.pub2 PMC6768987

222. Triolo G Ferrante A Ciccia F Accardo-Palumbo A Perino A Castelli A Giarratano A Licata G Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies Arthritis Rheum 2003 48 728 731 10.1002/art.10957 12632426

223. Branch DW Peaceman AM Druzin M Silver RK El-Sayed Y Silver RM Esplin MS Spinnato J Harger J A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group Am J Obstet Gynecol 2000 182 122 127 10.1016/S0002-9378(00)70500-X 10649166

224. Vaquero E Lazzarin N Valensise H Menghini S Di Pierro G Cesa F Romanini C Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin Am J Reprod Immunol 2001 45 174 179 10.1111/j.8755-8920.2001.450309.x 11270643

225. Clark AL Branch DW Silver RM Harris EN Pierangeli S Spinnato JA Pregnancy complicated by the antiphospholipid syndrome: outcomes with intravenous immunoglobulin therapy Obstet Gynecol 1999 93 437 441 10.1016/S0029-7844(98)00437-2 10074995

226. Sher G Matzner W Feinman M Maassarani G Zouves C Chong P Ching W The selective use of heparin/aspirin therapy, alone or in combination with intravenous immunoglobulin G, in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization Am J Reprod Immunol 1998 40 74 82 9764348 10.1111/j.1600-0897.1998.tb00394.x

227. Marzusch K Dietl J Klein R Hornung D Neuer A Berg PA Recurrent first trimester spontaneous abortion associated with antiphospholipid antibodies: a pilot study of treatment with intravenous immunoglobulin Acta Obstet Gynecol Scand 1996 75 922 926 10.3109/00016349609055029 9003094

228. Valensise H Vaquero E De Carolis C Stipa E Perricone R Arduini D Romanini C Normal fetal growth in women with antiphospholipid syndrome treated with high-dose intravenous immunoglobulin (IVIG) Prenat Diagn 1995 15 509 517 10.1002/pd.1970150603 7659685

229. Hockel M Queisser-Luft A Beck T Zielberg R Stopfkuchen H Lissner R The effect of antenatal intravenous immunoglobulin on ascending intrauterine infection after preterm premature rupture of the membranes: a pilot study J Perinat Med 1992 20 101 110 10.1515/jpme.1992.20.2.101 1501052

230. Clark DA Coulam CB Stricker RB Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF) J Assist Reprod Genet 2006 23 1 13 10.1007/s10815-005-9013-1 16421767 PMC3455429

231. Stephenson MD Fluker MR Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial Fertil Steril 2000 74 1108 1113 10.1016/S0015-0282(00)01622-8 11119735

232. Bozkurt B Villaneuva FS Holubkov R Tokarczyk T Alvarez RJ Jr MacGowan GA Murali S Rosenblum WD Feldman AM McNamara DM Intravenous immune globulin in the therapy of peripartum cardiomyopathy J Am Coll Cardiol 1999 34 177 180 10.1016/S0735-1097(99)00161-8 10400008

233. Kishimoto C Shioji K Kinoshita M Iwase T Tamaki S Fujii M Murashige A Maruhashi H Takeda S Nonogi H Hashimoto T Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress Int J Cardiol 2003 91 173 178 10.1016/S0167-5273(03)00002-0 14559127

234. Drucker NA Colan SD Lewis AB Beiser AS Wessel DL Takahashi M Baker AL Perez-Atayde AR Newburger JW Gamma-globulin treatment of acute myocarditis in the pediatric population Circulation 1994 89 252 257 8281654 10.1161/01.cir.89.1.252

235. Durongpisitkul K Gururaj VJ Park JM Martin CF The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment Pediatrics 1995 96 1057 1061 7491221

236. Oates-Whitehead RM Baumer JH Haines L Love S Maconochie IK Gupta A Roman K Dua JS Flynn I Intravenous immunoglobulin for the treatment of Kawasaki disease in children Cochrane Database Syst Rev 2003 4 CD004000 14584002 10.1002/14651858.CD004000 PMC6544780

237. Newburger JW Takahashi M Burns JC Beiser AS Chung KJ Duffy CE Glode MP Mason WH Reddy V Sanders SP The treatment of Kawasaki syndrome with intravenous gamma globulin N Engl J Med 1986 315 341 347 2426590 10.1056/NEJM198608073150601

238. Khowsathit P Hong-Hgam C Khositseth A Wanitkun S Treatment of Kawasaki disease with a moderate dose (1 g/kg) of intravenous immunoglobulin J Med Assoc Thai 2002 85 Suppl 4 S1121 S1126 12549785

239. Tsai MH Huang YC Yen MH Li CC Chiu CH Lin PY Lin TY Chang LY Clinical responses of patients with Kawasaki disease to different brands of intravenous immunoglobulin J Pediatr 2006 148 38 43 10.1016/j.jpeds.2005.08.024 16423595

240. Qin LJ Wang HW Hu XF Liu QJ Shi H Wei YX Chen QJ Cheng PX Therapeutic effectiveness of intravenous immunoglobulin at 1 g/kg and 2 g/kg on Kawasaki disease: a comparative and follow-up study Zhonghua Er Ke Za Zhi 2006 44 891 895 17254453

241. Sakata K Hamaoka K Ozawa S Niboshi A Yoshihara T Nishiki T Nakagawa Y Kazuta K Morimoto Y Kamiya Y Yamamoto T Horii Y Kido S A randomized prospective study on the use of 2 g-IVIG or 1 g-IVIG as therapy for Kawasaki disease Eur J Pediatr 2007 166 565 571 10.1007/s00431-006-0280-3 17103193

242. Newburger JW Takahashi M Beiser AS Burns JC Bastian J Chung KJ Colan SD Duffy CE Fulton DR Glode MP A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome N Engl J Med 1991 324 1633 1639 1709446 10.1056/NEJM199106063242305

243. Voss LM Wilson NJ Neutze JM Whitlock RM Ameratunga RV Cairns LM Lennon DR Intravenous immunoglobulin in acute rheumatic fever: a randomized controlled trial Circulation 2001 103 401 406 11157692 10.1161/01.cir.103.3.401

244. John R Lietz K Burke E Ankersmit J Mancini D Suciu-Foca N Edwards N Rose E Oz M Itescu S Intravenous immunoglobulin reduces anti-HLA alloreactivity and shortens waiting time to cardiac transplantation in highly sensitized left ventricular assist device recipients Circulation 1999 100 II229 II235 10567309 10.1161/01.cir.100.suppl_2.ii-229

245. Drakos SG Kfoury AG Long JW Stringham JC Fuller TC Nelson KE Campbell BK Gilbert EM Renlund DG Low-dose prophylactic intravenous immunoglobulin does not prevent HLA sensitization in left ventricular assist device recipients Ann Thorac Surg 2006 82 889 893 10.1016/j.athoracsur.2006.04.017 16928502

246. Meyer SR Ross DB Forbes K Hawkins LE Halpin AM Nahirniak SN Rutledge JM Rebeyka IM Campbell PM Failure of prophylactic intravenous immunoglobulin to prevent sensitization to cryopreserved allograft tissue used in congenital cardiac surgery J Thorac Cardiovasc Surg 2007 133 1517 1523 10.1016/j.jtcvs.2006.12.019 17532950

247. Letko E Bhol K Foster CS Ahmed AR Linear IgA bullous disease limited to the eye: a diagnostic dilemma: response to intravenous immunoglobulin therapy Ophthalmology 2000 107 1524 1528 10.1016/S0161-6420(00)00245-1 10919903

248. Noseworthy JH O'Brien PC Petterson TM Weis J Stevens L Peterson WK Sneve D Cross SA Leavitt JA Auger RG Weinshenker BG Dodick DW Wingerchuk DM Rodriguez M A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis Neurology 2001 56 1514 1522 11402108 10.1212/wnl.56.11.1514

249. Roed HG Langkilde A Sellebjerg F Lauritzen M Bang P Morup A Frederiksen JL A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis Neurology 2005 64 804 810 15753413 10.1212/01.WNL.0000152873.82631.B3

250. Symon Z Schneebaum N Eyal A Tal S Rozen N Shoenfeld Y Successful intravenous immunoglobulin therapy for resistant inflammatory pseudotumor of the orbit Thyroid 2005 15 398 399 10.1089/thy.2005.15.398 15876167

251. Cassoux N Goichot-Bonnat L Karmochkine M Georges F Kullmann N Lehoang P Kazatchkine M Efficacy of intravenous immunoglobulin in the treatment of Birdshot retinochoroiditis J Fr Ophtalmol 2002 25 23 30 11965114

252. Shambal S Lindner A Zierz S Successful treatment of orbital myositis with intravenous immunoglobulins Muscle Nerve 1998 21 1359 1360 10.1002/(SICI)1097-4598(199810)21:10<1359::AID-MUS26>3.0.CO;2-W 9736075

253. Rosenbaum JT George RK Gordon C The treatment of refractory uveitis with intravenous immunoglobulin Am J Ophthalmol 1999 127 545 549 10.1016/S0002-9394(99)00029-X 10334347

254. Onal S Foster CS Ahmed AR Efficacy of intravenous immunoglobulin treatment in refractory uveitis Ocul Immunol Inflamm 2006 14 367 374 10.1080/09273940601025966 17162608

255. Baschieri L Antonelli A Nardi S Alberti B Lepri A Canapicchi R Fallahi P Intravenous immunoglobulin versus corticosteroid in treatment of Graves' ophthalmopathy Thyroid 1997 7 579 585 10.1089/thy.1997.7.579 9292946

256. Kahaly G Pitz S Muller-Forell W Hommel G Randomized trial of intravenous immunoglobulins versus prednisolone in Graves' ophthalmopathy Clin Exp Immunol 1996 106 197 202 10.1046/j.1365-2249.1996.d01-854.x 8918563 PMC2200583

257. Guy J Aptsiauri N Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases Arch Ophthalmol 1999 117 471 477 10206574 10.1001/archopht.117.4.471

258. Subhadra C Dudek AZ Rath PP Lee MS Improvement in visual fields in a patient with melanoma-associated retinopathy treated with intravenous immunoglobulin J Neuroophthalmol 2008 28 23 26 18347454 10.1097/WNO.0b013e31816754c4

259. Floccari F Cosentini V Giacobbe M Coppolino G Campo S Bolignano D Tripodo D Nostro L Buemi M A case-by-case protocol of membranous nephropathy treatment with endovenous infusion of high doses of human immunoglobulins Nephron Clin Pract 2008 108 c113 c120 10.1159/000113528 18212513

260. Palla R Cirami C Panichi V Bianchi AM Parrini M Grazi G Intravenous immunoglobulin therapy of membranous nephropathy: efficacy and safety Clin Nephrol 1991 35 98 104 2032403

261. Yokoyama H Goshima S Wada T Takaeda M Furuichi K Kobayashi K Kida H The short- and long-term outcomes of membranous nephropathy treated with intravenous immune globulin therapy. Kanazawa Study Group for Renal Diseases and Hypertension Nephrol Dial Transplant 1999 14 2379 2386 10.1093/ndt/14.10.2379 10528661

262. Rasche FM Keller F Lepper PM Aymanns C Karges W Sailer LC Muller L Czock D High-dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: a long-term follow-up Clin Exp Immunol 2006 146 47 53 10.1111/j.1365-2249.2006.03189.x 16968397 PMC1809721

263. Sener A House AA Jevnikar AM Boudville N McAlister VC Muirhead N Rehman F Luke PP Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients Transplantation 2006 81 117 120 10.1097/01.tp.0000181096.14257.c2 16421486

264. Sharma AP Moussa M Casier S Rehman F Filler G Grimmer J Intravenous immunoglobulin as rescue therapy for BK virus nephropathy Pediatr Transplant 2008 13 123 129 10.1111/j.1399-3046.2008.00958.x 18822106

265. Ito-Ihara T Ono T Nogaki F Suyama K Tanaka M Yonemoto S Fukatsu A Kita T Suzuki K Muso E Clinical efficacy of intravenous immunoglobulin for patients with MPO-ANCA-associated rapidly progressive glomerulonephritis Nephron Clin Pract 2006 102 c35 c42 10.1159/000088313 16174989

266. Basok A Shnaider A Tovbin D Rogachev B Successful use of high dose intravenous immunoglobulin in rapidly progressive crescentic glomerulonephritis with vasculitis Isr Med Assoc J 2001 3 453 454 11433643

267. Tuso P Moudgil A Hay J Goodman D Kamil E Koyyana R Jordan SC Treatment of antineutrophil cytoplasmic autoantibody-positive systemic vasculitis and glomerulonephritis with pooled intravenous gamma globulin Am J Kidney Dis 1992 20 504 508 1442764 10.1016/s0272-6386(12)70265-2

268. Billing H Rieger S Ovens J Susal C Melk A Waldherr R Opelz G Tonshoff B Successful treatment of chronic antibody-mediated rejection with IVIG and rituximab in pediatric renal transplant recipients Transplantation 2008 86 1214 1221 10.1097/TP.0b013e3181880b35 19005402

269. Yang YW Lin WC Wu MS Lee PH Tsai MK Early diagnosis and successful treatment of acute antibody-mediated rejection of a renal transplant Exp Clin Transplant 2008 6 211 214 18954299

270. Furth S Neu AM Hart J Zachary A Colombani P Fivush BA Plasmapheresis, intravenous cytomegalovirus-specific immunoglobulin and reversal of antibody-mediated rejection in a pediatric renal transplant recipient: a case report Pediatr Transplant 1999 3 146 149 10.1034/j.1399-3046.1999.00022.x 10389137

271. Jordan SC Quartel AW Czer LS Admon D Chen G Fishbein MC Schwieger J Steiner RW Davis C Tyan DB Posttransplant therapy using high-dose human immunoglobulin (intravenous gamma globulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action Transplantation 1998 66 800 805 10.1097/00007890-199809270-00017 9771846

272. Boletis JN Ioannidis JP Boki KA Moutsopoulos HM Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis Lancet 1999 354 569 570 10.1016/S0140-6736(99)01575-5 10470708

273. Levy Y Sherer Y George J Rovensky J Lukac J Rauova L Poprac P Langevitz P Fabbrizzi F Shoenfeld Y Intravenous immunoglobulin treatment of lupus nephritis Semin Arthritis Rheum 2000 29 321 327 10.1016/S0049-0172(00)80018-9 10805356

274. Meissner M Sherer Y Levy Y Chwalinska-Sadowska H Langevitz P Shoenfeld Y Intravenous immunoglobulin therapy in a patient with lupus serositis and nephritis Rheumatol Int 2000 19 199 201 10.1007/s002960000053 10984139

275. Arahata H Migita K Izumoto H Miyashita T Munakata H Nakamura H Tominaga M Origuchi T Kawabe Y Hida A Taguchi T Eguchi K Successful treatment of rapidly progressive lupus nephritis associated with anti-MPO antibodies by intravenous immunoglobulins Clin Rheumatol 1999 18 77 81 10.1007/s100670050060 10088959

276. Razzaque Ahmed A Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment J Am Acad Dermatol 2001 45 679 690 10.1067/mjd.2001.116339 11606916

277. Baum S Scope A Barzilai A The role of IVIG treatment in severe pemphigus vulgaris J Eur Acad Dermatol Venereol 2006 20 548 552 10.1111/j.1468-3083.2006.01540.x 16684282

278. Bystryn JC Jiao D Natow S Treatment of pemphigus with intravenous immunoglobulin J Am Acad Dermatol 2002 47 358 363 10.1067/mjd.2002.122735 12196744

279. Sami N Qureshi A Ruocco E Corticosteroid-sparing effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris Arch Dermatol 2002 138 1158 1162 10.1001/archderm.138.9.1158 12224976

280. Wetter DA Davis MD Yiannias J Effectiveness of intravenous immunoglobulin therapy for skin disease other than Toxic Epidermal Necrolysis: a retrospective review of Mayo Clinic experience Mayo Clinic Proc 2005 80 41 47 10.4065/80.1.41 15667028

281. Razzaque Ahmed A Sami N Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional treatment J Am Acad Dermatol 2002 46 42 49 10.1067/mjd.2002.116338 11756944

282. Sami N Bhol KC Razzaque Ahmed A Influence of IVIg therapy on autoantibody titers to desmoglein 1 in patients with pemphigus foliaceus Clin Immunol 2002 105 192 198 10.1006/clim.2002.5278 12482393

283. Sami N Qureshi A Razzaque Ahmed A Steroid sparing effect of intravenous immunoglobulin therapy in patients with pemphigus foliaceus Eur J Dermatol 2002 12 174 178 11872417

284. Razzaque Ahmed A Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment J Am Acad Dermatol 2001 45 825 835 10.1067/mjd.2001.116337 11712025

285. Engineer L Razzaque Ahmed A Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: analysis of current data J Am Acad Dermatol 2001 44 83 88 11148470 10.1067/mjd.2000.112288

286. Sami N Bhol KC Razzaque Ahmed A Treatment of oral pemphigoid with intravenous immunoglobulin as monotherapy. Long-term follow-up: influence of treatment on antibody titers to human alpha6 integrin Clin Exp Immunol 2002 129 533 540 10.1046/j.1365-2249.2002.01942.x 12197896 PMC1906475

287. Hern S Harman K Bhogal BS A severe persistent case of pemphigoid gestationis treated with intravenous immunoglobulin and cyclosporin Clin Exp Dermatol 1998 23 185 188 10.1046/j.1365-2230.1998.00342.x 9894365

288. Prins C Vittorio C Padilla RS Effect of high-dose intravenous immunoglobulin therapy in Stevens–Johnson syndrome: a retrospective, multicenter study Dermatology 2003 207 96 99 10.1159/000070957 12835566

289. Morici MV Wesley G Shetty AK Intravenous immunoglobulin therapy for children with Stevens–Johnson syndrome J Rheumatol 2000 27 2494 2497 11036849

290. Al-Mutairi N Arun J Osama NE Prospective, noncomparative open study from Kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal necrolysis Int J Dermatol 2004 43 847 851 10.1111/j.1365-4632.2004.02048.x 15533072

291. Campione E Marulli GC Carrozzo AM High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis Acta Derm Venereol 2003 83 430 432 14690337 10.1080/0001550310005852

292. Bachot N Revuz J Roujeau JC Intravenous immunoglobulin treatment for Stevens–Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression Arch Dermatol 2003 139 33 36 10.1001/archderm.139.1.33 12533161

293. Spornraft-Ragaller P Theilen H Gottschlich GS Ragaller M Treatment of toxic epidermal necrolysis. Experience with 9 patients with consideration of intravenous immunoglobulin Hautarzt 2006 57 185 194 10.1007/s00105-006-1104-0 16501921

294. Nasser M Bitterman-Deutsch O Nassar F Intravenous immunoglobulin for treatment of toxic epidermal necrolysis Am J Med Sci 2005 329 95 98 10.1097/00000441-200502000-00007 15711426

295. Metry D 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 1430 1436 10.1542/peds.112.6.1430 14654625

296. Prins C Kerdel FA Padilla RS Treatment of toxic epidermal necrolysis with high dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases Arch Dermatol 2003 139 26 32 10.1001/archderm.139.1.26 12533160

297. Trent JT Kirsner RS Romanelli P Kerdel FA Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: the University of Miami Experience Arch Dermatol 2003 139 39 43 10.1001/archderm.139.1.39 12533162

298. Tristani-Firouzi P Petersen MJ Saffle JR Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children J Am Acad Dermatol 2002 47 548 552 10.1067/mjd.2002.127249 12271299

299. Shortt R Gomez M Mittman N Cartotto R Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis J Burn Care Rehabil 2004 25 246 255 10.1097/01.BCR.0000124746.33279.86 15273465

300. Paul C Lahfa M Bachelez H A randomized controlled evaluator-blinded trial of intravenous immunoglobulin in adults with severe atopic dermatitis Br J Dermatol 2002 147 518 522 10.1046/j.1365-2133.2002.04833.x 12207594

301. Jolles S Sewell C Webster D Adjunctive high-dose intravenous immunoglobulin treatment for resistant atopic dermatitis: efficacy and effects on intracellular cytokine levels and CD4 counts Acta Derm Venereol 2003 83 433 437 10.1080/00015550310020549 14690338

302. Jolles S Hughes J Rustin M The treatment of atopic dermatitis with adjunctive high dose intravenous immunoglobulin: a report of three patients and review of the literature Br J Dermatol 2000 142 551 554 10.1046/j.1365-2133.2000.03377.x 10735971

303. Wakim M Alazard M Yajima A High dose immunoglobulin in atopic dermatitis and hyper-IgE syndrome Ann Allergy Asthma Immunol 1998 81 153 158 10.1016/S1081-1206(10)62802-5 9723561

304. Jolles S A review of high-dose intravenous immunoglobulin treatment for atopic dermatitis Clin Exp Dermatol 2002 27 3 7 10.1046/j.0307-6938.2001.00955.x 11952659

305. O'Donnell BF Barr RM Black AK Intravenous immunoglobulin un autoimmune chronic urticaria Br J Dermatol 1998 138 101 106 10.1046/j.1365-2133.1998.02033.x 9536230

306. Kroiss M Vogt T Landthaler M The effectiveness of low dose intravenous immunoglobulin in chronic urticaria Acta Derm Venereol 2000 80 225 10.1080/000155500750012540 10954227

307. Dawn G Urcelay M Ah-Weng A Effect of high-dose intravenous immunoglobulin delayed pressure urticaria Br J Dermatol 2003 149 836 840 10.1046/j.1365-2133.2003.05486.x 14616377

308. Puech-Plottova I Michel JL Rouchouse B Solar urticaria: one case treated by intravenous immunoglobulin Ann Dermatol Venereol 2000 127 831 835 11060387

309. Darras S Ségrad M Mortier L Treatment of solar urticaria by intravenous immunoglobulins and PUVA therapy Ann Dermatol Venereol 2004 131 65 69 10.1016/S0151-9638(04)93546-6 15041848

310. Orson FM Intravenous immunoglobulin therapy suppresses manifestations of the angioedema with hypereosinophilia syndrome Am J Med Sci 2003 326 94 97 10.1097/00000441-200308000-00007 12920441

311. Gurmin V Mediwake R Fernando M Psoriasis: response to high-dose intravenous immunoglobulin in three patients Br J Dermatol 2002 147 554 557 10.1046/j.1365-2133.2002.04753.x 12207600

312. Cummins DL Anhalt GJ Monahan T Meyerle JH Treatment of pyoderma gangrenosum with intravenous immunoglobulin Br J Dermatol 2007 157 1235 1239 10.1111/j.1365-2133.2007.08217.x 17916196

313. Meyer N Ferraro V Mignard MH Pyoderma gangrenosum treated with high-dose intravenous immunoglobulins: two cases and review of literature Clin Drug Investig 2006 26 541 546 10.2165/00044011-200626090-00007 17163287

314. Chung HJ Chung KY Nephrogenic fibrosing dermopathy: response to high-dose intravenous immunoglobulin Br J Dermatol 2004 150 596 597 10.1111/j.1365-2133.2003.05795.x 15030351

315. Antonelli A Navarranne A Palla R Pretibial myxedema and high-dose intravenous immunoglobulin treatment Thyroid 1994 4 399 408 10.1089/thy.1994.4.399 7711502

316. Blum M Wigley FM Hummers LK Scleromyxedema. A case series highlighting long-term outcomes of treatment with intravenous immunoglobulin (IVIG) Medicine 2008 87 10 20 10.1097/MD.0b013e3181630835 18204366

317. Kulczycki A Nelson M Eisen A Heffernan M Scleromyxoedema: treatment of cutaneous and systemic manifestations with high-dose intravenous immunoglobulin Br J Dermatol 2003 149 1276 1281 10.1111/j.1365-2133.2003.05682.x 14674909

318. Lister RK Jolles S Whittaker S Black C Forgacs I Cramp M Potter M Rustin MH Scleromyxedema: response to high-dose intravenous immunoglobulin (hdIVIg) J Am Acad Dermatol 2000 43 403 408 10.1016/S0190-9622(00)70305-7 10901735

319. Gholam P Hartmann M Enk A Arndt–Gottron scleromyxedema: successful therapy with intravenous immunoglobulins Br J Dermatol 2007 157 1058 1060 10.1111/j.1365-2133.2007.08169.x 17854360

320. Majeski C Taher M Grewal P Combination oral prednisone and intravenous immunoglobulin in the treatment of scleromyxedema J Cutan Med Surg 2005 9 99 104 10.1007/s10227-005-0137-9 16392012

321. Körber A Franckson T Grabbe S Dissemond J Successful therapy of scleromyxedema Arndt–Gottron with low-dose intravenous immunoglobulin Eur Acad Dermatol Venereol 2007 21 553 554 10.1111/j.1468-3083.2006.01951.x 17373996

322. Topf S Simon M Schell H Lüftl M Marked improvement in scleromyxedema with high-dose immunoglobulin Hautarzt 2007 58 525 528 10.1007/s00105-006-1261-1 17165069

323. Wojas-Pelc A Błaszczyk M Glinska M Jabłonska S Tumorous variant of scleromyxedema. Successful therapy with intravenous immunoglobulins Eur Acad Dermatol Venereol 2005 19 462 465 10.1111/j.1468-3083.2005.01134.x 15987294

324. Jolles S Hughes J Use of IGIV in the treatment of atopic dermatitis, urticaria, scleromyxedema, pyoderma gangrenosum, psoriasis, and pretibial myxedema Int Immunopharmacol 2006 6 579 591 10.1016/j.intimp.2005.11.017 16504920

325. Boonyaleepun S Boonyaleepun C Schlactus JL Effect of IVIG on the hair regrowth in a common variable immune deficiency patient with alopecia universalis Asian Pac J Allergy Immunol 1999 17 59 62 10403010

326. Carmeli Y Mevorach D Kaminski N Raz E Regression of Kaposi's sarcoma after intravenous immunoglobulin treatment for polymyositis Cancer 1994 73 2859 2891 10.1002/1097-0142(19940601)73:11<2859::AID-CNCR2820731132>3.0.CO;2-P 8194027

327. Schachter J Katz U Mahrer A Efficacy and safety of intravenous immunoglobulin in patients with metastatic melanoma Ann N Y Acad Sci 2007 1110 305 314 10.1196/annals.1423.032 17911445

328. Plevova P Blazek B Intravenous immunoglobulin as prophylaxis of chemotherapy-induced oral mucositis J Natl Cancer Inst 1997 89 326 327 10.1093/jnci/89.4.326 9048841

329. Murie-Fernandez M Gurpide A de la Cruz S de Castro P Total remission of thymus carcinoma after treatment with intravenous immunoglobulin Clin Transl Oncol 2006 8 697 699 10.1007/s12094-006-0043-7 17005475

330. Agarwal S Cunningham-Rundles C Thymoma and immunodeficiency (Good syndrome): a report of 2 unusual cases and review of the literature Ann Allergy Asthma Immunol 2007 98 185 190 10.1016/S1081-1206(10)60695-3 17304889 PMC3102047

331. Sharma KR Cross J Ayyar DR Diabetic demyelinating polyneuropathy responsive to intravenous immunoglobulin therapy Arch Neurol 2002 59 751 757 10.1001/archneur.59.5.751 12020256

332. Kawagashira Y Watanabe H Oki Y Intravenous immunoglobulin therapy markedly ameliorates muscle weakness and severe pain in proximal diabetic neuropathy J Neurol Neurosurg Psychiatry 2007 78 899 901 10.1136/jnnp.2006.111302 17635982 PMC2117752

333. Uluduz D Bozluolcay M Ince B Kiziltan M Simultaneous multiple cranial nerve neuropathies and intravenous immunoglobulin treatment in diabetes mellitus Neurol India 2005 54 308 309 10.4103/0028-3886.27163 16936399

334. Wada Y Yanagihara C Nishimura Y Oka N A case of diabetic amyotrophy with severe atrophy and weakness of shoulder girdle muscles showing good response to intravenous immune globulin Diabetes Res Clin Pract 2007 75 107 110 10.1016/j.diabres.2006.05.006 16781792

335. Melcher M Olson JL Baxter-Lowe LA Antibody-mediated rejection of a pancreas allograft Am J Transplant 2006 6 423 428 10.1111/j.1600-6143.2005.01185.x 16426331

336. Reisin R Zurrú C Buso C Multifocal motor neuropath, type 1 diabetes and asymptomatic Hashimoto's thyroiditis: an unusual association Neuromuscul Disord 2005 15 358 360 10.1016/j.nmd.2005.01.008 15833429

337. Toscano A Rodolico C Benvenga S Multifocal motor neuropathy and asymptomatic Hashimoto's thyroiditis: first report of association Neuromuscul Disord 2002 12 566 568 10.1016/S0960-8966(01)00311-X 12117481

338. Yuceyar N Karadeniz M Erdogan M Thyrotoxic autoimmune encephalopathy in a female patient: only partial response to typical immunosuppressant treatment and remission after thyroidectomy Clin Neurol Neurosurg 2007 109 458 462 10.1016/j.clineuro.2007.02.006 17395366

339. Cappa M Bertini E Del Balzo P High dose immunoglobulin IV treatment in adrenoleukodystrophy J Neurol Neurosurg Psychiatry 1994 57 Supplement 69 70 10.1136/jnnp.57.Suppl.69 7964860 PMC1016731

340. Kohler W Discussion on: high dose immunoglobulin IV treatment in adrenoleukodystrophy J Neurol Neurosurg Psychiatry 1994 57 Suppl 71 10.1136/jnnp.57.Suppl.71 PMC1016731 7964860

341. Agraharkar M Fahlen M Siddiqui M Waterhouse–Friderichsen syndrome and bilateral renal cortical necrosis in meningococcal sepsis Am J Kidney Disease 2000 36 396 400 10.1053/ajkd.2000.8994 10922319

342. Antonelli A Gambuzza C Alberti B Autoimmune polyendocrine syndrome. Treatment with intravenous immunoglobulins Clin Ther 1992 141 43 48 1468197

343. Leen WG Weemaes CM Verbeek MM Willemsen MA Rotteveel JJ Rituximab and intravenous immunoglobulins for relapsing postinfectious opsoclonus-myoclonus syndrome Pediatr Neurol 2008 39 213 217 10.1016/j.pediatrneurol.2008.05.015 18725071

344. Unal A Sumer MM Atasoy HT Atasoy N Treatment of idiopathic opsoclonus-myoclonus syndrome with intravenous immunoglobulin Neurol India 2004 52 520 521 15626860

345. Glatz K Meinck HM Wildemann B Parainfectious opsoclonus-myoclonus syndrome: high dose intravenous immunoglobulins are effective J Neurol Neurosurg Psychiatry 2003 74 279 280 10.1136/jnnp.74.2.279 12531974 PMC1738269

346. Pranzatelli MR Tate ED Kinsbourne M Caviness VS Jr Mishra B Forty-one year follow-up of childhood-onset opsoclonus-myoclonus-ataxia: cerebellar atrophy, multiphasic relapses, and response to IVIG Mov Disord 2002 17 1387 1390 10.1002/mds.10283 12465092

347. Borgna-Pignatti C Balter R Marradi P Colamaria V Treatment with intravenously administered immunoglobulins of the neuroblastoma-associated opsoclonus-myoclonus J Pediatr 1996 129 179 180 8757589 10.1016/s0022-3476(96)70225-1

348. Pless M Ronthal M Treatment of opsoclonus-myoclonus with high-dose intravenous immunoglobulin Neurology 1996 46 583 584 8614543 10.1212/wnl.46.2.583-a

349. Petruzzi MJ de Alarcon PA Neuroblastoma-associated opsoclonus-myoclonus treated with intravenously administered immune globulin G J Pediatr 1995 127 328 329 10.1016/S0022-3476(95)70322-5 7636667

350. Sugie H Sugie Y Akimoto H Endo K Shirai M Ito M High-dose i.v. human immunoglobulin in a case with infantile opsoclonus polymyoclonia syndrome Acta Paediatr 1992 81 371 372 10.1111/j.1651-2227.1992.tb12248.x 1606405

351. Bataller L Graus F Saiz A Vilchez JJ Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus Brain 2001 124 437 443 10.1093/brain/124.2.437 11157570

352. Perlmutter SJ Leitman SF Garvey MA Hamburger S Feldman E Leonard HL Swedo SE Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood Lancet 1999 354 1153 1158 10.1016/S0140-6736(98)12297-3 10513708

353. Fazekas F Lublin FD Li D Freedman MS Hartung HP Rieckmann P Sorensen PS Maas-Enriquez M Sommerauer B Hanna K Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial Neurology 2008 71 265 271 10.1212/01.wnl.0000318281.98220.6f 18645164

354. Pohlau D Przuntek H Sailer M Bethke F Koehler J Konig N Heesen C Spath P Andresen I Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study Mult Scler 2007 13 1107 1117 10.1177/1352458507078400 17623736

355. Petereit HF Reske D Pukrop R Maas-Enriquez M Japp G Jongen PJ Kolmel HW Merkelbach S Hartung HP Heiss WD Hommes OR No effect of intravenous immunoglobulins on cytokine-producing lymphocytes in secondary progressive multiple sclerosis Mult Scler 2006 12 66 71 10.1191/135248506ms1246oa 16459721

356. Haas J Maas-Enriquez M Hartung HP Intravenous immunoglobulins in the treatment of relapsing remitting multiple sclerosis—results of a retrospective multicenter observational study over five years Mult Scler 2005 11 562 567 10.1191/1352458505ms1224oa 16193894

357. Hommes OR Sorensen PS Fazekas F Enriquez MM Koelmel HW Fernandez O Pozzilli C O'Connor P Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial Lancet 2004 364 1149 1156 10.1016/S0140-6736(04)17101-8 15451222

358. Sorensen PS Fazekas F Lee M Intravenous immunoglobulin G for the treatment of relapsing–remitting multiple sclerosis: a meta-analysis Eur J Neurol 2002 9 557 563 10.1046/j.1468-1331.2002.00501.x 12453069

359. Fazekas F Strasser-Fuchs S Hartung HP Intravenous immunoglobulins in therapy of intermittent multiple sclerosis. An update Nervenarzt 1998 69 361 365 10.1007/s001150050284 9606690

360. Achiron A Gabbay U Gilad R Hassin-Baer S Barak Y Gornish M Elizur A Goldhammer Y Sarova-Pinhas I Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses Neurology 1998 50 398 402 9484361 10.1212/wnl.50.2.398

361. Sorensen PS Wanscher B Schreiber K Blinkenberg M Jensen CV Ravnborg M A double-blind, cross-over trial of intravenous immunoglobulin G in multiple sclerosis: preliminary results Mult Scler 1997 3 145 148 10.1177/135245859700300216 9291170

362. Hughes RA Swan AV Raphael JC Annane D van Koningsveld R van Doorn PA Immunotherapy for Guillain–Barré syndrome: a systematic review Brain 2007 130 2245 2257 10.1093/brain/awm004 17337484

363. Yata J Nihei K Ohya T Hirano Y Momoi M Maekawa K Sakakihara Y High-dose immunoglobulin therapy for Guillain–Barré syndrome in Japanese children Pediatr Int 2003 45 543 549 10.1046/j.1442-200X.2003.01768.x 14521529

364. Raphael JC Chevret S Harboun M Jars-Guincestre MC Intravenous immune globulins in patients with Guillain–Barré syndrome and contraindications to plasma exchange: 3 days versus 6 days J Neurol Neurosurg Psychiatry 2001 71 235 238 10.1136/jnnp.71.2.235 11459901 PMC1737513

365. Kuwabara S Mori M Ogawara K Hattori T Oda S Koga M Yuki N Intravenous immunoglobulin therapy for Guillain–Barré syndrome with IgG anti-GM1 antibody Muscle Nerve 2001 24 54 58 10.1002/1097-4598(200101)24:1<54::AID-MUS6>3.0.CO;2-9 11150966

366. Plasma Exchange/Sandoglobulin Guillain–Barré Syndrome Trial Group Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain–Barré syndrome Lancet 1997 349 225 230 10.1016/S0140-6736(96)09095-2 9014908

367. van der Meche FG Intravenous immune globulin in the Guillain–Barré syndrome Clin Exp Immunol 1994 97 Suppl 1 43 47 8033434 PMC1550365

368. Lunn MP Nobile-Orazio E Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies Cochrane Database Syst Rev 2006 2 CD002827 16625561 10.1002/14651858.CD002827.pub2

369. Comi G Roveri L Swan A Willison H Bojar M Illa I Karageorgiou C Nobile-Orazio E van den Bergh P Swan T Hughes R Aubry J Baumann N Hadden R Lunn M Knapp M Leger JM Bouche P Mazanec R Meucci N van der Meche F Toyka K A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy J Neurol 2002 249 1370 1377 10.1007/s00415-002-0808-z 12382151

370. Dalakas MC Quarles RH Farrer RG Dambrosia J Soueidan S Stein DP Cupler E Sekul EA Otero C A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy Ann Neurol 1996 40 792 795 10.1002/ana.410400516 8957021

371. Meucci N Nobile-Orazio E Scarlato G Intravenous immunoglobulin therapy in amyotrophic lateral sclerosis J Neurol 1996 243 117 120 10.1007/BF02444000 8750546

372. Dalakas MC Stein DP Otero C Sekul E Cupler EJ McCrosky S Effect of high-dose intravenous immunoglobulin on amyotrophic lateral sclerosis and multifocal motor neuropathy Arch Neurol 1994 51 861 864 8080385 10.1001/archneur.1994.00540210031010

373. Bain PG Motomura M Newsom-Davis J Misbah SA Chapel HM Lee ML Vincent A Lang B Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert–Eaton myasthenic syndrome Neurology 1996 47 678 683 8797464 10.1212/wnl.47.3.678

374. Karlson EW Sudarsky L Ruderman E Pierson S Scott M Helfgott SM Treatment of stiff-man syndrome with intravenous immune globulin Arthritis Rheum 1994 37 915 918 10.1002/art.1780370621 8003064

375. Amato AA Cornman EW Kissel JT Treatment of stiff-man syndrome with intravenous immunoglobulin Neurology 1994 44 1652 1654 7936291 10.1212/wnl.44.9.1652

376. Khanlou H Eiger G Long-term remission of refractory stiff-man syndrome after treatment with intravenous immunoglobulin Mayo Clin Proc 1999 74 1231 1232 10.4065/74.12.1231 10593352

377. Dalakas MC Fujii M Li M Lutfi B Kyhos J McElroy B High-dose intravenous immune globulin for stiff-person syndrome N Engl J Med 2001 345 1870 1876 10.1056/NEJMoa01167 11756577

378. Cappa M Bertini E del Balzo P Cambiaso P Di Biase A Salvati S High dose immunoglobulin IV treatment in adrenoleukodystrophy J Neurol Neurosurg Psychiatry 1994 57 Suppl 69 70 10.1136/jnnp.57.Suppl.69 7964860 PMC1016731

379. van Rijckevorsel-Harmant K Delire M Schmitz-Moorman W Wieser HG Treatment of refractory epilepsy with intravenous immunoglobulins. Results of the first double-blind/dose finding clinical study Int J Clin Lab Res 1994 24 162 166 10.1007/BF02592447 7819596

380. Illum N Taudorf K Heilmann C Smith T Wulff K Mansa B Platz P Intravenous immunoglobulin: a single-blind trial in children with Lennox–Gastaut syndrome Neuropediatrics 1990 21 87 90 10.1055/s-2008-1071468 2193242

381. Mohr M Englisch L Roth A Burchardi H Zielmann S Effects of early treatment with immunoglobulin on critical illness polyneuropathy following multiple organ failure and gram-negative sepsis Intensive Care Med 1997 23 1144 1149 10.1007/s001340050471 9434920

382. Wijdicks EF Fulgham JR Failure of high dose intravenous immunoglobulins to alter the clinical course of critical illness polyneuropathy Muscle Nerve 1994 17 1494 1495 7969261

383. Granata T Fusco L Gobbi G Freri E Ragona F Broggi G Mantegazza R Giordano L Villani F Capovilla G Vigevano F Bernardina BD Spreafico R Antozzi C Experience with immunomodulatory treatments in Rasmussen's encephalitis Neurology 2003 61 1807 1810 14694056 10.1212/01.wnl.0000099074.04539.e0

384. Villani F Spreafico R Farina L Giovagnoli AR Bernasconi P Granata T Avanzini G Positive response to immunomodulatory therapy in an adult patient with Rasmussen's encephalitis Neurology 2001 56 248 250 11160964 10.1212/wnl.56.2.248

385. Leach JP Chadwick DW Miles JB Hart IK Improvement in adult-onset Rasmussen's encephalitis with long-term immunomodulatory therapy Neurology 1999 52 738 742 10078719 10.1212/wnl.52.4.738

386. Hart YM Cortez M Andermann F Hwang P Fish DR Dulac O Silver K Fejerman N Cross H Sherwin A Medical treatment of Rasmussen's syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients Neurology 1994 44 1030 1036 8208394 10.1212/wnl.44.6.1030

387. Hughes RA Donofrio P Bril V Dalakas MC Deng C Hanna K Hartung HP Latov N Merkies IS van Doorn PA Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial Lancet Neurol 2008 7 136 144 10.1016/S1474-4422(07)70329-0 18178525

388. Hughes R Bensa S Willison H Van den Bergh P Comi G Illa I Nobile-Orazio E van Doorn P Dalakas M Bojar M Swan A Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy Ann Neurol 2001 50 195 201 10.1002/ana.1088 11506402

389. Mendell JR Barohn RJ Freimer ML Kissel JT King W Nagaraja HN Rice R Campbell WW Donofrio PD Jackson CE Lewis RA Shy M Simpson DM Parry GJ Rivner MH Thornton CA Bromberg MB Tandan R Harati Y Giuliani MJ Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy Neurology 2001 56 445 449 11222785 10.1212/wnl.56.4.445

390. Hahn AF Bolton CF Zochodne D Feasby TE Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study Brain 1996 119 Pt 4 1067 1077 10.1093/brain/119.4.1067 8813271

391. Gajdos P Chevret S Toyka K Intravenous immunoglobulin for myasthenia gravis Cochrane Database Syst Rev 2008 2 CD002277 10.1002/14651858.CD002277.pub3 18254004

392. Zinman L Ng E Bril V IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial Neurology 2007 68 837 841 10.1212/01.wnl.0000256698.69121.45 17353471

393. Wolfe GI Barohn RJ Foster BM Jackson CE Kissel JT Day JW Thornton CA Nations SP Bryan WW Amato AA Freimer ML Parry GJ Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis Muscle Nerve 2002 26 549 552 10.1002/mus.10224 12362423

394. Ronager J Ravnborg M Hermansen I Vorstrup S Immunoglobulin treatment versus plasma exchange in patients with chronic moderate to severe myasthenia gravis Artif Organs 2001 25 967 973 10.1046/j.1525-1594.2001.06717.x 11843764

395. Achiron A Barak Y Miron S Sarova-Pinhas I Immunoglobulin treatment in refractory myasthenia gravis Muscle Nerve 2000 23 551 555 10.1002/(SICI)1097-4598(200004)23:4<551::AID-MUS14>3.0.CO;2-O 10716766

396. Fu DC Montgomery JR High-dose, rapid-infusion IVIG in postvaccination acute disseminated encephalomyelitis Neurology 2008 71 294 295 10.1212/01.wnl.0000318277.25679.9e 18645168

397. Shahar E Andraus J Savitzki D Pilar G Zelnik N Outcome of severe encephalomyelitis in children: effect of high-dose methylprednisolone and immunoglobulins J Child Neurol 2002 17 810 814 10.1177/08830738020170111001 12585719

398. Marchioni E Marinou-Aktipi K Uggetti C Bottanelli M Pichiecchio A Soragna D PiccoloG IF Romani A Ceroni M Effectiveness of intravenous immunoglobulin treatment in adult patients with steroid-resistant monophasic or recurrent acute disseminated encephalomyelitis J Neurol 2002 249 100 104 10.1007/PL00007836 11954856

399. Straussberg R Schonfeld T Weitz R Karmazyn B Harel L Improvement of atypical acute disseminated encephalomyelitis with steroids and intravenous immunoglobulins Pediatr Neurol 2001 24 139 143 10.1016/S0887-8994(00)00229-0 11275464

400. Andersen JB Rasmussen LH Herning M Paerregaard A Dramatic improvement of severe acute disseminated encephalomyelitis after treatment with intravenous immunoglobulin in a three-year-old boy Dev Med Child Neurol 2001 43 136 138 10.1017/S0012162201220258 11221905

401. Sahlas DJ Miller SP Guerin M Veilleux M Francis G Treatment of acute disseminated encephalomyelitis with intravenous immunoglobulin Neurology 2000 54 1370 1372 10746613 10.1212/wnl.54.6.1370

402. DelGiudice-Asch G Simon L Schmeidler J Cunningham-Rundles C Hollander E Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism J Autism Dev Disord 1999 29 157 160 10.1023/A:1023096728131 10382136

403. Quartier P Debre M de Blic J Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients J Pediatr 1999 134 589 596 10.1016/S0022-3476(99)70246-5 10228295

404. Liese JG Wintergerst U Tympner KD Belohradsky BH High- vs. low-dose immunoglobulin therapy in the long-term treatment of X-linked agammaglobulinemia Am J Dis Child 1992 146 335 339 1543181 10.1001/archpedi.1992.02160150075025

405. Aghamohammadi A Moin M Farhoudi A Efficacy of intravenous immunoglobulin on the prevention of pneumonia in patients with agammaglobulinemia FEMS Immunol Med Microbiol 2004 40 113 118 10.1016/S0928-8244(03)00304-3 14987729

406. Nolte MT Pirofsky B Gerritz GA Golding B Intravenous immunoglobulin therapy for antibody deficiency Clin Exp Immunol 1979 36 237 243 477026 PMC1537711

407. Eijkhout HW van der Meer JWM Kallenberg CGM The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia Ann Int Med 2001 135 165 174 11487483 10.7326/0003-4819-135-3-200108070-00008

408. Litzman J Jones A Hann I Intravenous immunoglobulin, splenectomy and antibiotic prophylaxis in Wiscott–Aldrich syndrome Arch Dis Child 1996 75 436 439 10.1136/adc.75.5.436 8957959 PMC1511781

409. Matamoros Flori N Mila Llambi J Hernandez Gonzalez M Julia Benique MR New diagnostic and therapeutic aspects of hyper-IgE syndrome. Report of 3 cases Med Clin (Barc) 1993 101 138 140 8355543

410. DeWitt CA Bishop AB Buescher LS Stone SP Hyperimmunoglobulin E syndrome: two cases and a review of the literature J Am Acad Dermatol 2006 54 855 865 10.1016/j.jaad.2005.10.022 16635666

411. Wakim M Alazard M Yajima A Speights D Saxon A Stiehm ER High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome Ann Allergy Asthma Immunol 1998 81 153 158 10.1016/S1081-1206(10)62802-5 9723561

412. Shield JP Strobel S Levinsky RJ Morgan G Immunodeficiency presenting as hypergammaglobulinaemia with IgG2 subclass deficiency Lancet 1992 340 448 450 10.1016/0140-6736(92)91769-5 1354783

413. Grob M Joller-Jemelka HI Grob PJ Deficiency in immunoglobulin subclasses as cause of increased infection susceptibility—a family study Schweiz Med Wochenschr 1991 121 133 144 1900641

414. Chinratanapisit S Tunsuriyawong P Vichyanond P Visitsunthorn N Luangwedchakarn V Jirapongsananuruk O Chronic rhinosinusitis and recurrent nasal polyps in two children with IgG subclass deficiency and review of the literature J Med Assoc Thai 2005 88 Suppl 8 S251 S258 16856448

415. Nettagul R Visitsunthorn N Vichyanond P A case of IgG subclass deficiency with the initial presentation of transient hypogamma immunoglobulinemia of infancy and a review of IgG subclass deficiencies J Med Assoc Thai 2003 86 686 692 12948264

416. Nordin U Wannfors K Colque-Navarro P Mollby R Heimdahl A Antibody response in patients with osteomyelitis of the mandible Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995 79 429 435 10.1016/S1079-2104(05)80122-2 7614200

417. Cheng YK Decker PA O'Byrne MM Weiler CR Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome Ann Allergy Asthma Immunol 2006 97 306 311 10.1016/S1081-1206(10)60794-6 17042135

418. Babovic-Vuksanovic D Jacobson RM Lindor NM Weiler CR Selective antibody immune deficiency in a patient with Smith–Lemli–Opitz syndrome J Inherit Metab Dis 2005 28 181 186 10.1007/s10545-005-5515-3 15877207

419. Quartier P Bustamante J Sanal O Plebani A Debre M Deville A Litzman J Levy J Fermand JP Lane P Horneff G Aksu G Yalcin I Davies G Tezcan I Ersoy F Catalan N Imai K Fischer A Durandy A Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency Clin Immunol 2004 110 22 29 10.1016/j.clim.2003.10.007 14962793

420. Bejaoui M Mellouli F Chouanine R Dellagi K Barbouche MR The hyper-IgM syndrome: 13 observations Presse Med 2003 32 544 549 12714921

421. Ersoy F Tezcan I Sanal O Effects of intravenous immunoglobulin on clinical and immunological findings of patients with humoral immunodeficiency diseases Turk J Pediatr 1992 34 203 209 1306339

422. Quezada A Norambuena X Gonzalez R Ramos SM Chavez A Gonzalez S Non-X-linked hyperimmunoglobulin M syndrome with chronic interstitial pneumonitis J Investig Allergol Clin Immunol 2000 10 375 379 11206940

423. Atarod L Aghamohammadi A Moin M Kanegane H Rezaei N Rezaei Kalantari K Amirzagar AA Futatani T Miyawaki M Successful management of neutropenia in a patient with CD40 ligand deficiency by immunoglobulin replacement therapy Iran J Allergy Asthma Immunol 2007 6 37 40 17303928

424. Ma YC Shyur SD Huang LH Wu JY Lin SC Hyper-IgM syndrome: report of one case Acta Paediatr Taiwan 2004 45 334 339 15868849

425. Hsueh KC Chiu HH Lin HC Hsu CH Tsai FJ Transient hypogammaglobulinemia of infancy presenting as Staphylococcus aureus sepsis with deep neck infection J Microbiol Immunol Infect 2005 38 141 144 15843860

426. Benderly A Pollack S Etzioni A Transient hypogammaglobulinemia of infancy with severe bacterial infections and persistent IgA deficiency Isr J Med Sci 1986 22 393 396 2427477

427. Buckley RH Schiff SE Schiff RI Markert L Williams LW Roberts JL Myers LA Ward FE Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency N Engl J Med 1999 340 508 516 10.1056/NEJM199902183400703 10021471

428. Busse PJ Razvi S Cunningham-Rundles C Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency J Allergy Clin Immunol 2002 109 1001 1004 10.1067/mai.2002.124999 12063531