Parenteral Immunoglobulins [Medicare]
Number: 0206m
Commercial CPB | Medicare CPB
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Medicare Part B Step Therapy Criteria
Asceniv, Bivigam, Cutaquig, Cuvitru, Flebogamma, Gammagard, Gammagard S/D, Gammaked, Gammaplex, Gamunex-C, Hyqvia, Octagam, Panzyga, and Xembify for the indications listed below:
- Primary Immunodeficiency (PI)
- Idiopathic Thrombocytopenic Purpura (ITP)
- Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Are not covered for new starts, unless the member meets ANY of the following:
- Inadequate response to a trial of Hizentra (Immune Globulin Subcutaneous (Human)) or Privigen (Immune Globulin Intravenous (Human)
- Intolerable adverse event to Hizentra (Immune Globulin Subcutaneous (Human)) or Privigen (Immune Globulin Intravenous (Human)
- Hizentra (Immune Globulin Subcutaneous (Human)) or Privigen (Immune Globulin Intravenous (Human) are contraindicated for the member.
Policy
Note: Requires Precertification:
Precertification of intravenous immunoglobulins (IVIG) [Asceniv, Bivigam, Flebogamma DIF, Gammagard Liquid, Gammagard S/D, Gammaked, Gammaplex, Gamunex-C, Octagam, Panzyga, and Privigen] and subcutaneous immunoglobulins (SCIG) [Cutaquig, Cuvitru, Hizentra, HyQvia, and Xembify] is required of all Aetna participating providers and members in applicable plan designs. For precertification of immunoglobulins , call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (888) 267-3277.
Note: Site of Care Utilization Management Policy applies to the IVIG and the SCIG products listed above. For information on site of service for Immunoglobulin infusions, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.
Intravenous Immunoglobulins (IVIG) and Subcutaneous Immunoglobulins (SCIG)
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Criteria for Initial Approval
Aetna considers the use of intravenous immunoglobulin (IVIG) therapy or subcutaneous immunoglobulin (SCIG) therapy medically necessary in members with the conditions specified below.
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Primary Immunodeficiency
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Severe combined immunodeficiency (SCID) or congenital agammaglobulinemia (eg, X-linked or autosomal recessive agammaglobulinemia):
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Diagnosis confirmed by genetic or molecular testing, or
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Pretreatment IgG level < 200 mg/dL, or
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Absence or very low number of T cells (CD3 T cells < 300/microliter) or the presence of maternal T cells in the circulation (SCID only);
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Wiskott-Aldrich syndrome, DiGeorge syndrome, or ataxia-telangiectasia (or other non-SCID combined immunodeficiency):
- Diagnosis confirmed by genetic or molecular testing (if applicable), and
- History of recurrent bacterial infections (e.g,, pneumonia, otitis media, sinusitis, sepsis, gastrointestinal), and
- Impaired antibody response to pneumococcal polysaccharide vaccine (see Appendix);
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Common variable immunodeficiency (CVID):
- Age 2 years or older; and
- Other causes of immune deficiency have been excluded (eg, drug induced, genetic disorders, infectious diseases such as HIV, malignancy); and
- Pretreatment IgG level < 500 mg/dL or ≥ 2 SD below the mean for age; and
- History of recurrent bacterial infections; and
- Impaired antibody response to pneumococcal polysaccharide vaccine (see Appendix);
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Hypogammaglobulinemia (unspecified), IgG subclass deficiency, selective IgA deficiency, selective IgM deficiency, or specific antibody deficiency:
- History of recurrent bacterial infections; and
- Impaired antibody response to pneumococcal polysaccharide vaccine (see Appendix); and
- Any of the following pre-treatment laboratory findings:
- Hypogammaglobulinemia: IgG < 500 mg/dL or ≥ 2 SD below the mean for age; or
- Selective IgA deficiency: IgA level < 7 mg/dL with normal IgG and IgM levels; or
- Selective IgM deficiency: IgM level < 30 mg/dL with normal IgG and IgA levels; or
- IgG subclass deficiency: IgG1, IgG2, or IgG3 ≥ 2 SD below mean for age assessed on at least 2 occasions; normal IgG (total) and IgM levels, normal/low IgA levels; or
- Specific antibody deficiency: normal IgG, IgA and IgM levels;
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Other predominant antibody deficiency disorders must meet the following criteria:
- History of recurrent bacterial infections; and
- Impaired antibody response to pneumococcal polysaccharide vaccine (see Appendix); and
- Hypogammaglobulinemia: IgG < 500 mg/dL or ≥ 2 SD below the mean for age
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Other combined immunodeficiency must meet the following criteria:
- Diagnosis confirmed by genetic or molecular testing (if applicable), and
- History of recurrent bacterial infections (eg, pneumonia, otitis media, sinusitis, sepsis, gastrointestinal), and
- Impaired antibody response to pneumococcal polysaccharide vaccine (see Appendix);
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Continuation of therapy for primary immunodeficiency disorders - continued treatment is considered medically necessary for primary immunodeficiency disorders when the following criteria are met:
- A reduction in the frequency of bacterial infections has been demonstrated since initiation of IVIG or SCIG therapy, and
- IgG trough levels are monitored at least yearly and maintained at or above the lower range of normal for age (when applicable for indication), or
- The prescriber will re-evaluate the dose of IVIG or SCIG and consider a dose adjustment (when appropriate).
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Myasthenia Gravis
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Short-term therapy is considered medically necessary for one month for members who are prescribed IVIG or SCIG for worsening weakness, acute exacerbation, or in preparation for surgery:
- Worsening weakness includes an increase in any of the following symptoms: diplopia, ptosis, blurred vision, difficulty speaking (dysarthria), difficulty swallowing (dysphagia), difficulty chewing, impaired respiratory status, fatigue, and limb weakness. Acute exacerbations include more severe swallowing difficulties and/or respiratory failure; or
- Pre-operative management (eg, prior to thymectomy);
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IVIG or SCIG therapy is considered medically necessary for members with refractory myasthenia gravis who have tried and failed 2 or more of standard therapies (e.g., corticosteroids, azathioprine, cyclosporine, mycophenolate mofetil, rituximab).
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Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
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Initial therapy is considered medically necessary when the following criteria are met:
- Disease course is progressive or relapsing/remitting for 2 months or longer; and
- Moderate to severe functional disability; and
- The diagnosis was confirmed by electrodiagnostic studies;
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Continued treatment is considered medically necessary when the following criteria are met:
- Significant improvement in disability and maintenance of improvement since initiation of IVIG or SCIG therapy; and
- IVIG or SCIG is being used at the lowest effective dose and frequency.
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Dermatomyositis or Polymyositis
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Initial therapy is considered medically necessary when the following criteria are met:
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Member has at least 4 of the following:
- Proximal muscle weakness (upper or lower extremity and trunk)
- Elevated serum creatine kinase (CK) or aldolase level
- Muscle pain on grasping or spontaneous pain
- Myogenic changes on EMG (short-duration, polyphasic motor unit potentials with spontaneous fibrillation potentials)
- Positive anti-Jo-1 (histadyl tRNA synthetase) antibody
- Non-destructive arthritis or arthralgias
- Systemic inflammatory signs (fever: more than 37°C at axilla, elevated serum CRP level or accelerated ESR of more than 20 mm/h by the Westergren method,
- Pathological findings compatible with inflammatory myositis (inflammatory infiltration of skeletal evidence of active regeneration may be seen), and
- Standard first-line treatments (corticosteroids) and second-line treatments (immunosuppressants) have been tried but were unsuccessful or not tolerated, or
- Member is unable to receive standard first-line and second-line therapy because of a contraindication or other clinical reason;
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Continued therapy is considered medically necessary when the following criterion is met: Significant improvement in disability and maintenance of improvement since initiation of IVIG or SCIG therapy.
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Idiopathic Thrombocytopenic Purpura ITP/(Immune Thrombocytopenia)
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Newly diagnosed ITP (diagnosed within the past 3 months) or initial therapy is considered medically necessary when the following criteria are met:
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Children (< 18 years of age)
- Significant bleeding symptoms (mucosal bleeding or other moderate/severe bleeding); or
- High risk for bleeding (see Appendix), or
- Rapid increase in platelets is required (e.g., surgery or procedure);
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Adults (≥ 18 years of age)
- Platelet count < 30,000/mcL, or
- Platelet count < 50,000/mcL and significant bleeding symptoms, high risk for bleeding or rapid increase in platelets is required, and
- Corticosteroid therapy is contraindicated and IVIG or SCIG will be used alone or IVIG or SCIG will be used in combination with corticosteroid therapy;
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Chronic/persistent ITP (≥ 3 months from diagnosis) or ITP unresponsive to first-line therapy: considered medically necessary when the following criteria are met:
- Platelet count < 30,000/mcL, or
- Platelet count < 50,000/mcL and significant bleeding symptoms, high risk for bleeding or rapid increase in platelets is required, and
- Relapse after previous response to IVIG or SCIG or inadequate response/intolerance/contraindication to corticosteroid or anti-D therapy;
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Adults with refractory ITP after splenectomy: considered medically necessary when either of the following criteria is met:
- Platelet count < 30,000/mcL, or
- Significant bleeding symptoms;
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ITP in pregnant women: considered medically necessary through delivery for pregnant women with ITP
For ITP indications based upon high risk of bleeding, the member’s risk factor(s) for bleeding (see Appendix) or reason requiring a rapid increase in platelets must be provided.
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B-cell Chronic Lymphocytic Leukemia (CLL)
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Initial therapy is considered medically necessary when all of the following criteria are met:
- IVIG or SCIG is prescribed for prophylaxis of bacterial infections; and
- Member has a history of recurrent sinopulmonary infections requiring intravenous antibiotics or hospitalization; and
- Member has a pretreatment serum IgG level <500 mg/dL;
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Continued therapy is considered medically necessary when a reduction in the frequency of bacterial infections has been demonstrated since initiation of IVIG or SCIG therapy.
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Prophylaxis of Bacterial Infections in HIV-Infected Pediatric Members
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Initial therapy is considered medically necessary for pediatric members with HIV infection when any of the following criteria are met:
- IVIG or SCIG is prescribed for primary prophylaxis of bacterial infections and pretreatment serum IgG < 400 mg/dL, or
- IVIG or SCIG is prescribed for secondary prophylaxis of bacterial infections for members with a history of recurrent bacterial infections (> 2 serious bacterial infections in a 1-year period), or
- Member has failed to form antibodies to common antigens, such as measles, pneumococcal, and/or Haemophilus influenzae type b vaccine, or
- Member lives in an area where measles is highly prevalent and who have not developed an antibody response after two doses of measles, mumps, and rubella virus vaccine live, or
- Member has been exposed to measles and request is for a single dose, or
- Member has chronic bronchiectasis that is suboptimally responsive to antimicrobial and pulmonary therapy;
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Continued therapy is considered medically necessary when a reduction in the frequency of bacterial infections has been demonstrated since initiation of IVIG therapy.
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Bone Marrow Transplant/Hematopoietic Stem Cell Transplant (BMT/HSCT)
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Initial therapy is considered medically necessary for members who are BMT/HSCT recipients when the following criteria are met:
- IVIG or SCIG therapy will be used to prevent the risk of acute graft-versus-host disease, associated interstitial pneumonia (infectious or idiopathic), septicemia, and other infections (e.g., cytomegalovirus infections [CMV], recurrent bacterial infection); and
- Either of the following:
- IVIG or SCIG is requested within the first 100 days post-transplant; or
- Member has a pretreatment serum IgG < 400 mg/dL;
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Continued therapy is considered medically necessary when a reduction in the frequency of bacterial infections has been demonstrated since initiation of IVIG therapy.
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Multifocal Motor Neuropathy (MMN)
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Initial therapy is considered medically necessary when the following criteria are met:
- Member experienced progressive, multifocal, asymmetrical weakness without objective sensory loss in 2 or more nerves for at least 1 month; and
- The diagnosis was confirmed by electrodiagnostic studies;
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Continued therapy is considered medically necessary when significant improvement in disability and maintenance of improvement have occurred since initiation of IVIG or SCIG therapy.
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Guillain-Barre Syndrome (GBS)
Therapy for up to 1 month total is considered medically necessary for GBS when the following criteria are met:
- Member has severe disease with significant weakness (e.g., inability to stand or walk without aid, respiratory weakness); and
- Onset of neurologic symptoms occurred less than 4 weeks from the anticipated start of therapy.
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Lambert-Eaton Myasthenic Syndrome (LEMS)
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Initial therapy for LEMS is considered medically necessary when the following criteria are met:
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Diagnosis has been confirmed by either of the following:
- Neurophysiology studies (e.g., electromyography); or
- A positive anti- P/Q type voltage-gated calcium channel antibody test; and
- Anticholinesterases (e.g., pyridostigmine) and amifampridine (e.g., 3,4-diaminopyridine phosphate, Firdapse) have been tried but were unsuccessful or not tolerated; and
- Weakness is severe or there is difficulty with venous access for plasmapheresis;
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Continued IVIG therapy is considered medically necessary when member is responding to therapy (i.e., there is stability or improvement in symptoms relative to the natural course of LEMS).
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Kawasaki Syndrome
IVIG therapy is considered medically necessary for pediatric members with Kawasaki syndrome.
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Fetal/Neonatal Alloimmune Thrombocytopenia (F/NAIT)
IVIG therapy is considered medically necessary for treatment of F/NAIT.
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Parvovirus B19-induced Pure Red Cell Aplasia (PRCA)
IVIG therapy is considered medically necessary for severe, refractory anemia associated with bone marrow suppression, with parvovirus B19 viremia.
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Stiff-person Syndrome
IVIG therapy is considered medically necessary for stiff-person syndrome when the following criteria are met:
- Diagnosis has been confirmed by anti-glutamic acid decarboxylase (GAD) antibody testing; and
- Member had an inadequate response to first-line treatment (benzodiazepines and/or baclofen).
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Management of immune checkpoint inhibitor-related toxicities
Therapy for 1 month is considered medically necessary for immune checkpoint-inhibitor toxicities when all of the following criteria are met:
- Member has experienced a moderate or severe adverse event to a PD-1 or PD-L1 inhibitor (e.g., pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab); and
- The offending medication has been held or discontinued; and
- Member experienced one or more of the following adverse events: myocarditis, bullous dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pneumonitis, myasthenia gravis, peripheral neuropathy, encephalitis, transverse myelitis, severe inflammatory arthritis, Guillain-Barre syndrome, or steroid-refractory myalgias or myositis.
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Acquired Red Cell Aplasia
Considered medically necessary for acquired red cell aplasia.
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Acute Disseminated Encephalomyelitis
Considered medically necessary for acute disseminated encephalomyelitis in members who have had an insufficient response or a contraindication to intravenous corticosteroid treatment.
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Autoimmune Mucocutaneous Blistering Disease
Considered medically necessary for autoimmune mucocutaneous blistering disease (includes pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, and epidermolysis bullosa aquisita) when the following criteria are met:
- Diagnosis has been proven by biopsy and confirmed by pathology report, and
- Condition is rapidly progressing, extensive or debilitating, and
- Member has failed or experienced significant complications (e.g., diabetes, steroid-induced osteoporosis) from standard treatment (corticosteroids, immunosuppressive agents).
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Autoimmune Hemolytic Anemia
Considered medically necessary for warm-type autoimmune hemolytic anemia in members who do not respond or have a contraindication to corticosteroids or splenectomy.
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Autoimmune Neutropenia
Considered medically necessary for autoimmune neutropenia where treatment with G-CSF (granulocyte colony stimulating factor) is not appropriate.
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Birdshot Retinochoroidopathy
Considered medically necessary for birdshot (vitiliginous) retinochoroidopathy that is not responsive to immunosuppressives (e.g., corticosteroids, cyclosporine).
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BK Virus Associated Nephropathy
Considered medically necessary for BK virus associated nephropathy.
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Churg-Strauss Syndrome
Considered medically necessary for severe, active Churg-Strauss syndrome as adjunctive therapy for members who have experienced failure, intolerance, or are contraindicated to other interventions.
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Enteroviral Meningoencephalitis
Considered medically necessary or severe cases of enteroviral meningoencephalitis.
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Hematophagocytic Lymphohistiocytosis (HLH) or Macrophage Activation Syndrome (MAS)
Considered medically necessary for treatment of hypogammaglobulinemia in HLH or MAS when total IgG is less than 400 mg/dL or two standard deviations below the mean for age.
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Hemolytic Disease of Newborn
Considered medically necessary for isoimmune hemolytic disease in neonates.
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HIV-associated Thrombocytopenia
Considered medically necessary for HIV-associated thrombocytopenia when the following criteria are met:
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Pediatric members with IgG < 400 mg/dL and has one of the following:
- 2 or more bacterial infections in a 1-year period despite antibiotic chemoprophylaxis with TMP-SMZ or another active agent, or
- Received 2 doses or measles vaccine and lives in a region with a high prevalence or measles, or
- HIV-associated thrombocytopenia despite anti-retroviral therapy, or
- Chronic bronchiectasis that is suboptimally responsive to antimicrobial and pulmonary therapy, or
- T4 cell count ≥ 200/mm3
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Adult members with significant bleeding, platelet count < 20,000/mcL, and failure of RhIG in Rh-positive persons.
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Hyperimmunoglobulinemia E Syndrome
Considered medically necessary to treat severe eczema in hyperimmunoglobulinemia E syndrome.
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Hypogammaglobulinemia from CAR-T therapy
Considered medically necessary for members with IgG < 400 mg/dL receiving treatment with CAR-T therapy (including but not limited to idecabtagen vicleucel [Abecma], tisagenlecleucel [Kymriah], or axicabtagene ciloleucel [Yescarta]).
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Multiple Myeloma
Considered medically necessary for multiple myeloma in members who have recurrent, serious infections despite the use of prophylactic antibiotics.
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Neonatal Hemochromatosis
Considered medically necessary for members who are pregnant with a history of pregnancy ending in documented neonatal hemochromatosis.
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Opsoclonus-myoclonus
Considered medically necessary for treatment of either of the following:
- Paraneoplastic opsoclonus-myoclonus-ataxia associated with neuroblastoma; or
- Refractory opsoclonus-myoclonus, as last-resort treatment.
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Post-transfusion Purpura
Considered medically necessary for post-transfusion purpura.
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Rasmussen Encephalitis
Considered medically necessary for Rasmussen encephalitis in members whose symptoms do not improve with anti-epileptic drugs and corticosteroids.
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Renal Transplantation
Considered medically necessary for members undergoing renal transplantation from a live donor with ABO incompatibility or positive cross match.
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Secondary Immunosuppression Associated with Major Surgery, Hematological Malignancy, Major Burns, and Collagen-Vascular Diseases
Considered medically necessary to prevent or modify recurrent bacterial or viral infections in members with secondary immunosuppression (IgG < 400 mg/dL) associated with major surgery, hematological malignancy, extensive burns, or collagen-vascular disease.
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Solid Organ Transplantation
Considered medically necessary for solid organ transplantation for allosensitized members.
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Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome
Considered medically necessary for severe cases of toxic epidermal necrolysis or Stevens-Johnson syndrome.
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Toxic Shock Syndrome
Considered medically necessary for staphylococcal or streptococcal toxic shock syndrome when the infection is refractory to several hours of aggressive therapy, an undrainable focus is present, or the member has persistent oliguria with pulmonary edema.
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Systemic Lupus Erythematosus
Considered medically necessary for severe, active SLE in members who have experienced inadequate response, intolerance or have a contraindication to first and second line therapies.
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Measles (Rubeola) Prophylaxis
Considered medically necessary for postexposure prophylaxis to prevent or modify symptoms of measles (rubeola) in susceptible members exposed to the disease less than 6 days previously.
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Tetanus Treatment and Prophylaxis
Considered medically necessary for treatment or postexposure prophylaxis of tetanus as an alternative when tetanus immune globulin (TIG) is unavailable.
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Varicella Prophylaxis
Considered medically necessary for for postexposure prophylaxis of varicella in susceptible individuals when varicella-zoster immune globulin (VZIG) is unavailable.
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Toxic Necrotizing Fasciitis Due To Group A Streptococcus
Considered medically necessary for members with fasciitis due to invasive streptococcal infection.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
Aetna considers the continuation of IVIG or SCIG therapy medically necessary when either of the following criteria is met:
- For conditions with continuation criteria listed above under Section I: Members who are currently receiving IVIG or SCIG must meet the applicable continuation criteria for continued medical necessity for the member’s condition; or
- For all other conditions, all members (including new members) must meet medical necessity for initial authorization criteria.
Intramuscular Immunoglobulins
For intramuscularly administered immunoglobulins (e.g., GamaSTAN see CPB 0544 - Immune Globulins for Post-exposure Prophylaxis.
For Immune Globulins for rubella (German measles), see CPB 0544 - Immune Globulins for Post-exposure Prophylaxis.See also Aetna Non-Medicare Prescription Drug Plan Specialty Pharmacy Clinical Policy Bulletins.
Dosage and Administration
For dosing recommendations, see prescribing information for individual products.
Experimental and Investigational
Aetna considers the use of IVIG and SCIG experimental and investigational for all other clinical conditions because its effectiveness for indications other than the ones listed above has not been established. See Appendix for a current list of such indications (not an all-inclusive list).
Background
U.S. Food and Drug Administration (FDA)-Approved Indications for Intravenous Immunoglobulins (IVIG)
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Asceniv (immune globulin intravenous [human] - slra)
Primary immunodeficiency
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Bivigam (immune globulin intravenous [human])
Primary immunodeficiency
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Flebogamma DIF (immune globulin intravenous [human])
- Primary immunodeficiency
- Idiopathic thrombocytopenic purpura
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Gammagard Liquid (immune globulin infusion [human])
- Primary immunodeficiency
- Multifocal motor neuropathy
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Gammagard S/D (immunoglobulin intravenous [human])
- Primary immunodeficiency
- Idiopathic thrombocytopenic purpura
- B-cell chronic lymphocytic leukemia (CLL)
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Gammaked (immune globulin injection [human])
- Primary immunodeficiency
- Idiopathic thrombocytopenic purpura
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
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Gammaplex (immune globulin intravenous [human])
- Primary immunodeficiency
- Idiopathic thrombocytopenic purpura
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Gamunex-C (immune globulin injection [human])
- Primary immunodeficiency
- Idiopathic thrombocytopenic purpura
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
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Octagam (immune globulin intravenous [human])
- Primary immunodeficiency
- Idiopathic thrombocytopenic purpura
- Dermatomyositis
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Panzyga (immune globulin intravenous [human])
- Primary immunodeficiency
- Idiopathic thrombocytopenic purpura
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
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Privigen (immune globulin intravenous [human])
- Primary immunodeficiency
- Idiopathic thrombocytopenic purpura
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
Note: CSL Behring decided to discontinue the production of Carimune NF (immune globulin intravenous [human]) in 3Q 2018 due to the preference among healthcare providers and patients for newer, more advanced immune globulin options (i.e., Privigen (immune globulin intravenous [human]), 10% liquid, and Hizentra (immune globulin subcutaneous [human]), 20% liquid.
Compendial Uses for Intravenous Immunoglobulins (IVIG)
- Prophylaxis of bacterial infections in pediatric human immunodeficiency virus (HIV) infection
- Bone marrow transplant (BMT)/hematopoietic stem cell transplant (HSCT)
- Polymyositis
- Myasthenia gravis
- Guillain-Barré syndrome
- Lambert-Eaton myasthenic syndrome
- Fetal/neonatal alloimmune thrombocytopenia
- Parvovirus B19-induced pure red cell aplasia
- Stiff-person syndrome
- Management of immune checkpoint inhibitor-related toxicities
- Acquired red cell aplasia
- Acute disseminated encephalomyelitis
- Autoimmune mucocutaneous blistering diseases
- Autoimmune hemolytic anemia
- Autoimmune neutropenia
- Birdshot retinochoroidopathy
- BK virus associated nephropathy
- Churg-Strauss Syndrome
- Enteroviral meningoencephalitis
- Hematophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS)
- Hemolytic disease of newborn
- HIV-associated thrombocytopenia
- Hyperimmunoglobulinemia E Syndrome
- Hypogammaglobulinemia from chimeric antigen receptor T (CAR-T) therapy
- Measles (Rubeola) prophylaxis
- Multiple myeloma
- Neonatal hemochromatosis, prophylaxis
- Opsoclonus-myoclonus
- Paraneoplastic opsonus-myoclonus ataxia associated with neuroblastoma
- Post-transfusion purpura
- Rasmussen encephalitis
- Renal transplantation from a live donor with ABO incompatibility or positive cross match
- Secondary immunosuppression associated with major surgery, hematological malignancy, major burns, and collagen-vascular diseases
- Solid organ transplantation, for allosensitized members
- Systemic lupus erythematosus (SLE)
- Tetanus treatment and prophylaxis
- Toxic epidermal necrolysis and Stevens-Johnson syndrome
- Toxic shock syndrome
- Toxic necrotizing fasciitis due to group A streptococcus
- Varicella prophylaxis
U.S. Food and Drug Administration (FDA)-Approved Indications for Subcutaneous Immunoglobulins (SCIG)
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Cutaquig (immune globulin subcutaneous [human] - hipp, 16.5% Solution)
Cutaquig is indicated as replacement therapy for primary humoral immunodeficiency (PI) in adults and pediatric patients 2 years of age and older.
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Cuvitru (immune globulin subcutaneous [human], 20% Solution)
Cuvitru is indicated as replacement therapy for primary humoral immunodeficiency in adult and pediatric patients two years of age and older.
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Hizentra (immune globulin subcutaneous [human], 20% Liquid)
- Hizentra is indicated as replacement therapy for primary humoral immunodeficiency in adults and pediatric patients 2 years of age and older.
- Hizentra is indicated for the treatment of adult patients with chronic inflammatory demyelinating polyneuropathy (CIDP) as maintenance therapy to prevent relapse of neuromuscular disability and impairment.
Limitations of Use:
Hizentra maintenance therapy in CIDP has been systematically studied for 6 months and for a further 12 months in a follow-up study. Maintenance therapy beyond these periods should be individualized based upon the patient’s response and need for continued therapy.
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HyQvia (immune globulin infusion 10% [human] with recombinant human hyaluronidase)
HyQvia is indicated for the treatment of primary immunodeficiency in adults.
Limitations of Use:
Safety and efficacy of chronic use of recombinant human hyaluronidase in HyQvia have not been established in conditions other than primary immunodeficiency.
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Xembify (immune globulin subcutaneous [human] - klhw, 20% Solution)
Xembify is indicated for treatment of primary humoral immunodeficiency (PI) in patients 2 years of age and older.
Compendial Uses for Subcutaneous Immunoglobulins (SCIG)
- Idiopathic thrombocytopenic purpura (ITP)
- Multifocal motor neuropathy
- Kawasaki syndrome
- B-cell chronic lymphocytic leukemia (CLL)
- Prophylaxis of bacterial infections in pediatric human immunodeficiency virus (HIV) infection
- Prophylaxis of bacterial infections in bone marrow transplant (BMT)/hematopoietic stem cell transplant (HSCT) recipients
- Dermatomyositis
- Polymyositis
- Myasthenia gravis
- Guillain-Barré syndrome
- Lambert-Eaton myasthenic syndrome
- Fetal/neonatal alloimmune thrombocytopenia
- Parvovirus B19-induced pure red cell aplasia
- Stiff-person syndrome
- Management of immune checkpoint inhibitor-related nervous system adverse events
- Acquired red cell aplasia
- Acute disseminated encephalomyelitis
- Autoimmune mucocutaneous blistering diseases
- Autoimmune hemolytic anemia
- Autoimmune neutropenia
- Birdshot retinochoroidopathy
- BK virus associated nephropathy
- Churg-Strauss Syndrome
- Enteroviral meningoencephalitis
- Hematophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS)
- Hemolytic disease of newborn
- HIV-associated thrombocytopenia
- Hyperimmunoglobulinemia E Syndrome
- Hypogammaglobulinemia from chimeric antigen receptor T (CAR-T) therapy
- Multiple myeloma
- Neonatal hemochromatosis, prophylaxis
- Opsoclonus-myoclonus
- Paraneoplastic opsonus-myoclonus ataxia associated with neuroblastoma
- Post-transfusion purpura
- Rasmussen encephalitis
- Renal transplantation from a live donor with ABO incompatibility or positive cross match
- Secondary immunosuppression associated with major surgery, hematological malignancy, major burns, and collagen-vascular diseases
- Solid organ transplantation, for allosensitized members
- Toxic epidermal necrolysis and Stevens-Johnson syndrome
- Toxic shock syndrome
- Systemic lupus erythematosus (SLE)
- Toxic necrotizing fasciitis due to group A streptococcus
IVIG (immune globulin) is a sterile, non‐pyrogenic solution of globulins containing many antibodies normally present in adult human blood. It is officially designated in the United States as IGIV but is commonly referred to as IVIG. Immune globulin intramuscular (IGIM), immune globulin intravenous (IGIV), and immune globulin subcutaneous are used as replacement therapy in individuals with primary immunodeficiency diseases. They provide a broad spectrum of IgG antibodies against a wide variety of bacterial and viral agents. IGIM and IGIV are also used to provide passive immunity in susceptible patients exposed to certain infectious diseases when there is no vaccine available for active immunization against the disease, when the susceptible patient is allergic to a vaccine component, or when there is insufficient time for active immunization to stimulate antibody production. In addition, certain IVIG (immune globulin) preparations are also used as replacement therapy in patients with antibody-deficiency syndromes, treatment of autoimmune diseases such as idiopathic thrombocytopenia purpura, and Kawasaki disease.
There are multiple immune globulin products from multiple manufacturers that are commercially available. It is made from large pools of human plasma. To prevent the transmission of human viruses, blood donors are screened and the manufacturing process employs several methods of viral inactivation. IVIG (immune globulin) products differ according to the viral inactivation process, sugar content, IgA content, dosage from (lyophilized or solution), dosage strength (5% or 10%) and storage requirements. Product selection is based on availability of immune globulin and patient characteristics. Examples of current FDA approved intravenous immune globulin (IVIG) products include Asceniv, Bivigam, Flebogamma, Gammagard, Gammaked, Gammaplex, Gamunex-C, Octagam, Panzyga, and Privigen. Cutaquig, Cuvitru, Hizentra, HyQvia, and Xembify are examples of commercially available products for subcutaneous administration. GamaSTAN and GamaSTAN S/D are examples of products for intramuscular administration.
Each product may have different FDA approved indications; thus, specific product information, product availability, and patient characteristics should be taken into account when selecting therapy. Some of the main FDA approved indications include the treatment of primary immune deficiency disorder, prevention of bacterial infection in patients with hypogammaglobulinemia due to B cell chronic lymphocytic leukemia, prevention of coronary artery aneurysms in Kawasaki disease, and increasing platelet count in idiopathic thrombocytopenic purpura to prevent bleeding.
When a patient has a rapidly progressive disease where a clinical response cannot be affected quickly enough using conventional agents, immune globulin can be given along with conventional treatment(s). The continued administration of immune globulin is not considered medically necessary once conventional therapy takes effect.
Subcutaneous administration of immune globulin is an alternative to intravenous therapy for patients who meet the medical necessity criteria for intravenous immune globulin.
Once IVIG (immune globulin) treatment is initiated, there should be adequate documentation of progress and clinical monitoring.
Administration of IVIG (immune globulin) should not exceed the recommended rate of infusion, which is 4 mg/kg/min. Vital signs should be monitored continuously during infusion of IVIG (immune globulin) and the patient observed throughout the infusion.
Urine output and renal function (BUN and serum creatinine) should be assessed prior to and at appropriate intervals during IVIG (immune globulin) therapy. To minimize the risk of acute renal, patients should be adequately hydrated prior to IVIG (immune globulin) administration. Patients at risk for developing acute renal failure include those with any preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia, those receiving nephrotoxic drugs and those over the age of 65 years.
Patients with thrombotic risk factors, including advanced age, hypertension, cerebrovascular disease, coronary artery disease, diabetes mellitus, high serum levels of a monoclonal protein, a history of prolonged immobilization, and/or a history of thrombotic episodes should be evaluated before IVIG (immune globulin) administration due to the risk of developing thrombotic events.
Patients should also be monitored for clinical signs and symptoms of hemolysis and adverse pulmonary reactions.
Because IVIG (immune globulin) is prepared from pooled human plasma, there is the potential risk for transmission of human viruses including viral hepatitis, HIV, and Creutzfeldt‐Jakob disease.
Contraindications to IVIG (immune globulin) therapy include previous anaphylactic or severe systemic reactions to IVIG (immune globulin) and IgA deficient patients with antibodies against IgA and a history of hypersensitivity.
Intravenous immunoglobulin (IVIG) has been shown to be ineffective for the prophylaxis of, and as a treatment adjunct in, infections in some high-risk, preterm, low-birth-weight neonates (USPDI, 2002). Studies published before 1990 suggested that prophylactic IVIG reduced nosocomial infections in low-birth-weight infants. However, these studies enrolled small numbers of patients; employed varied designs, preparations, and doses; and included diverse study populations. The National Institute of Child Health and Human Development (NICHHD) Neonatal Research Network therefore performed a prospective, multi-center, randomized trial to test the hypothesis that the intravenous administration of immune globulin to infants with birth weights between 501 and 1,500 grams would reduce the incidence of nosocomial infections (Fanaroff et al, 1994). In this trial, the repeated prophylactic administration of IVIG failed to reduce the incidence of nosocomial infections significantly in premature infants weighing 501 to 1,500 grams at birth. Furthermore, there were no significant differences in morbidity, mortality, or the duration of hospitalization between infants given IVIG and infants given no infusion or an infusion and placebo.
For a discussion of IVIG for recurrent spontaneous abortion, see CPB 0348 - Recurrent Pregnancy Loss.
Several brands of IVIG have been approved by the Food and Drug Adminsitration (FDA) (see table in Appendix). There is a lack of reliable evidence that any one brand of IVIG is more effective than other brands. However, immune globulin products may differ from each other in ways that may be important in a particular patient. Different manufacturers then use various combinations of precipitation and/or chromatography steps to obtain a final preparation that consists of greater than 95 % IgG in all currently available products. The various manufacturers also use different final purification steps and stabilizers to obtain their final products, which may then vary in storage requirement and shelf life. In several currently available products, stabilizers include sugars, such as sucrose, glucose, or maltose. Other products contain amino acids such as glycine and proline. The sodium content of different products also varies.
Most products approximate the distribution of IgG subclasses found in normal plasma. However, products are neither standardized nor routinely tested for their content of specific antibodies against different pathogens, except for measles, poliovirus, and hepatitis B surface antigen.
Thus, product-to-product and lot-to-lot variation in specific antibody titers is likely. There are also product-to-product and lot-to-lot variations in adverse effects in individual patients. Thus, generic substitution is not acceptable for many patients. In contrast, the different preparations are generally assumed to have overall equivalent therapeutic efficacy in protecting antibody deficient patients against infection.
Specific patients may require, or do better with, IGIV products with certain characteristics. Most patients tolerate most products with a minimum of adverse events, or with simple premedications. Thus, for many patients, selection of a product to conform with local dispensing or formulary preferences may not pose problems. However, some patients experience a different range and/or severity of adverse effects from different products, which may be impossible to predict.
If a patient is having adverse effects that interfere with IgG replacement, different products should be tried in the hope of finding a product that will be more acceptable. However, adverse effects may be more frequent and/or more severe whenever a patient is first started on IGIV and whenever a new product is used. For this reason, extra caution should be used when starting a naïve patient or changing the specific product used by any individual patient.
Some patients require products low in IgA, or products with relatively lower osmolarity, sucrose, or sodium. Patients with diabetes who use certain types of glucose meters must use caution with maltose-containing products, since that sugar may give false readings for glucose. Some preparations may have as much as 30 mg/ml (3 %) albumin, in addition to the IgG itself. This may be undesirable in patients who might have trouble tolerating increased intravascular volume.
The first type of IgG preparation to be used for antibody replacement, 16 % Immune Serum Globulin (ISG) for intra-muscular (IM) administration is still available. However, the IM route is rarely used at the present time because the injections are painful, the amount given is limited by the volumes that can be administered, and there is risk of local injury, such as nerve damage.
Immune globulin may also been given by the subcutaneous route. Immune globulin may be administered by a subcutaneous injection via a small, portable pump for the prevention of serious infection in children and adults with primary immunodeficiency. Many patients can be readily taught to infuse themselves at home, or parents may administer the infusions to their children.
In April 2006, the American Academy of Asthma, Allergy and Immunology (Orange et al, 2006) published evidence based guidelines on indications for intravenous immunoglobulins.
Darabi et al (2006) noted that IVIG has been approved by the FDA for use in 6 conditions:- immune thrombocytopenic purpura (ITP),
- primary immunodeficiency,
- secondary immunodeficiency,
- pediatric HIV infection,
- Kawasaki disease, and
- prevention of graft-versus-host disease (GVHD) and infection in bone marrow transplant recipients.
IVIG has subsequently been approved by the FDA for chronic inflammatory demyelinating polyneuropathy (CIDP). However, most usage of IVIG is for off-label indications, and for some of these comprehensive guidelines have been published. Common off-labeled uses for IVIG include chronic neuropathy (e.g., multi-focal motor neuropathy), hypogammaglobulinemia, renal transplant rejection, myasthenia gravis, Guillain-Barre syndrome, necrotizing fasciitis, and autoimmune hemolytic anemia. The authors concluded that only a few indications account for most of the usage for IVIG. Reports concerning IVIG continue to grow at a tremendous pace but few high-quality randomized controlled studies have been reported. A position statement from the American Academy of Asthma, Allergy and Immunology (Orange, et al., 2005) states that "the decision to administer IGIV to patients with primary deficiencies in antibody production should be based on:
- abnormalities of serum immunoglobulin concentrations;
- clinical history of infections; and, when appropriate, and
- the demonstrated inability to produce antibody normally following antigenic stimulation.
"Guidelines from the American Academy of Asthma, Allergy & Immunology (Orange, et al., 2006) state; "Reduced levels of serum immunoglobulin in patients with recurrent bacterial infections coupled with a lack of response to protein or polysaccharide vaccine challenges (ie, patients who cannot make IgG antibody against diphtheria and tetanus toxoids, pneumococcal polysaccharide vaccine, or both) is a clear indication for IgG replacement.
In a review on autism, Levy et al (2009) stated that popular biologically based treatments include anti-infectives, chelation medications, gastrointestinal medications, hyperbaric oxygen therapy, and IVIGs. Non-biologically based treatments include auditory integration therapy, chiropractic therapy, cranio-sacral manipulation, interactive metronome, and transcranial stimulation. However, few studies have addressed the safety and effectiveness of most of these treatments.
Whitington and Kelly (2008) stated that neonatal hemochromatosis (NH) is the result of severe fetal liver injury that seems to result from maternal-fetal alloimmunity. Women who have had an infant affected with NH are at high-risk in subsequent pregnancies for having another affected infant. This study was designed to examine if therapy directed at limiting the severity of gestational alloimmunity can reduce the occurrence of severe NH in infants of women at risk. A secondary objective was to use a prospectively collected data set to examine questions of vital interest about NH. Women with a history of pregnancy ending in documented NH were treated with IVIG at 1 g/kg of body weight weekly from the 18th week until the end of gestation. Extensive data were prospectively collected regarding the gestational histories of the subjects. The outcomes of treated pregnancies were compared with those of previous affected pregnancies, which were used as historical controls. A total of 48 women were enrolled to be treated during 53 pregnancies. The gestational histories of these women demonstrated the high-risk of occurrence of NH: 92 % of pregnancies at risk resulted in intrauterine fetal demise, neonatal death, or liver failure necessitating transplant. In contrast, with gestational therapy, the 53 at-risk gestations resulted in 3 failures and 52 infants who survived intact with medical therapy alone. When compared on a per-woman or per-infant basis, the outcome of gestation at risk for NH was improved by gestational therapy. The authors concluded that NH seems to be the result of a gestational alloimmune disease, and occurrence of severe NH in at-risk pregnancies can be significantly reduced by treatment with high-dose IVIG during gestation.
In this regard, the Australian National Blood Authority (Gibson et al, 2007) listed NH as one of the conditions for which IVIG has an established therapeutic role. According to the Australian agency, women who are pregnant or attempting to conceive and their most recent pregnancy ended in delivery of a fetus shown to have had NH are qualified for IVIG therapy. Dosage should be 1g/kg body weight weekly from the 18th week until the end of gestation.
Anderson et al (2007) noted that to help ensure IVIG use is in keeping with an evidence-based approach to the practice of medicine, the National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for hematologic conditions. The mandate of the expert panel was to review evidence regarding use of IVIG for 18 hematologic conditions and formulate recommendations on IVIG use for each. A panel of 13 clinical experts and 1 expert in practice guideline development met to review the evidence and reach consensus on the recommendations for the use of IVIG. The primary sources used by the panel were 3 recent evidence-based reviews. Recommendations were based on interpretation of the available evidence and where evidence was lacking, consensus of expert clinical opinion. A draft of the practice guideline was circulated to hematologists in Canada for feedback. The results of this process were reviewed by the expert panel, and modifications to the draft guideline were made where appropriate. This practice guideline provided the NAC with a basis for making recommendations to provincial and territorial health ministries regarding IVIG use management. Specific recommendations for routine use of IVIG were made for 7 conditions including acquired red cell aplasia; acquired hypogammaglobulinemia (secondary to malignancy); fetal-neonatal alloimmune thrombocytopenia; hemolytic disease of the newborn; HIV-associated thrombocytopenia; idiopathic thrombocytopenic purpura; and post-transfusion purpura. Intravenous immune globulin was not recommended for use, except under certain life-threatening circumstances, for 8 conditions including acquired hemophilia; acquired von Willebrand disease; autoimmune hemolytic anemia; autoimmune neutropenia; hemolytic transfusion reaction; hemolytic transfusion reaction associated with sickle cell disease; hemolytic uremic syndrome/thrombotic thrombocytopenic purpura; and viral-associated hemophagocytic syndrome. Intravenous immune globulin was not recommended for 2 conditions (aplastic anemia and hematopoietic stem cell transplantation) and was contraindicated for 1 condition (heparin-induced thrombocytopenia). For most hematologic conditions reviewed by the expert panel, routine use of IVIG was not recommended.
Goebel et al (2010) evaluated the effectiveness of IVIG in patients with longstanding complex regional pain syndrome (CRPS) under randomized, controlled conditions. Patients who had pain intensity greater than 4 on an 11-point (0 to 10) numerical rating scale and had CRPS for 6 to 30 months that was refractory to standard treatment were enrolled in this study. Subjects received IVIG (0.5 g/kg) and normal saline in separate treatments, divided by a washout period of at least 28 days. The primary outcome was pain intensity 6 to 19 days after the initial treatment and the cross-over treatment. A total of 13 eligible participants were randomly assigned and 12 completed the trial. The average pain intensity was 1.55 units lower after IVIG treatment than after saline (95 % confidence interval [CI]: 1.29 to 1.82; p < 0.001). In 3 patients, pain intensity after IVIG was less than after saline by 50 % or more. No serious adverse reactions were reported. The drawbacks of this study were that the trial was small, and recruitment bias and chance variation could have influenced results and their interpretation. The authors concluded that IVIG (0.5 g/kg) can reduce pain in refractory CRPS. They stated that confirmatory trials are required to ascertain the best immunoglobulin dose, the duration of effect, the need for repeat treatment, and whether treatment response varies with disease duration.
Diabetic amyotrophy usually occurs in patients with poorly controlled diabetes, either as an initial presentation or in a patient with longstanding disease. The mechanism of diabetic amyotrophy is uncertain, although peri-vascular inflammation and secondary nerve infarction are thought responsible. A recent consensus statement from the American Academy of Neurology (AAN) concluded that there is "no convincing data" to substantiate the treatment of diabetic amyotrophy using IVIG (Donofrio et al, 2009).
O'Horo and Safdar (2009) stated that clostridium difficile (C. difficile) is the most common infectious cause of nosocomial healthcare-associated diarrhea. The increasing prevalence of C difficile, spread in the community, virulence and frequent relapse has created an urgent need to identify new effective treatments for C. difficile infection. Among these, IVIG is used for cases of severe C. difficile infection. These investigators undertook a systematic review to examine the published literature pertaining to the use of immunoglobulin for C. difficile infection. Four retrospective studies and 5 case reports that addressed the use of IVIG for the treatment of C. difficile infection were identified. One study on the use of oral immunoglobulin was identified. Although overall there appear to be benefits to using IVIG in recurrent severe disease, the small sample sizes and lack of control groups in 3 of the 4 studies do not allow recommendations to be made regarding the use of immunoglobulin in C. difficile infection. The authors stated that further research is urgently needed to clarify the role of immunoglobulin -- intravenous or oral -- for the treatment of C. difficile infection.
Abougergi et al (2010) stated that C. difficile colitis (CDC) is the most common cause of hospital-acquired diarrhea. The increase in the incidence and fatality rate of CDC over the past decade has stimulated a search for new therapies, including IVIG. These researchers reported their experience with IVIG for the treatment of 21 patients with severe CDC. The existing literature on IVIG infusion for severe CDC was also reviewed. Twenty-one of 1,230 patients with CDC were treated with IVIG. The mean age was 68 (range of 35 to 98) years, with mean hospital stay of 23 (range of 9 to 64) days. Conventional treatment was used for an average of 8 (range of 1 to 25) days before IVIG infusion. All patients had evidence of pancolitis (radiologically) or ileus (clinically). The mean Acute Physiological Assessment and Chronic Health Evaluation (APACHE II) score was 25 (range of 6 to 39) at day 1 of IVIG infusion. Nine patients (43 %) survived their hospitalization with colitis resolution while 12 (57 %) died. One patient developed pulmonary edema after IVIG infusion. Symptoms resolved after an average of 10 (range of 2 to 20) days for survivors. Two patients underwent urgent colectomy. The authors concluded that this is the largest case series describing IVIG use for patients with severe CDC and the one with the highest mortality rate to date. The use of IVIG in this setting does not seem to benefit all patients. Benefit appears to depend on the extent of systemic involvement. They stated that further studies are needed before adopting IVIG as routine treatment for severe CDC.
Diaz-Manera and colleagues (2009) noted that advances in the treatment of myasthenia gravis (MG) have reduced mortality rates due to the disease and improved patients' quality of life. Nowadays, attending neurologists can choose among different treatment strategies for MG patients. An exhaustive revision of published data on the efficacy of the different therapeutic options for MG indicates that there are insufficient evidence-based results. However, recommendations based on expert opinion can be provided. Thymectomy is indicated in all patients with a thymoma or for generalized acetylcholine receptor-sero-positive patients aged 18 to 55 years. Steroids are the most widely used immunosuppressive drug for MG. They are recommended as the first-line drug in all patients with generalized MG without response to thymectomy, or in those patients who do not fulfill criteria for the surgery. The selection of second-line drugs may vary between protocols. The authors recommended starting with azathioprine if insufficient remission is achieved with steroids, followed by ciclosporin, mycophenolate and others. They use rituximab or cyclophosphamide only in severely drug-resistant patients. Finally, the authors recommend IVIG or plasma exchange (PE) in MG crisis, or for unstable patients before thymectomy or in clinical exacerbations.
Tranchant (2009) stated that the purpose of the treatment of MG is to improve neuromuscular transmission, and to reduce the production or presence of the nicotinic acetylcholine receptor (achR). Acetylcholinesterase inhibitors are the first line treatment with the rapid onset of effect, for all types of MG (ocular, generalized MG, sero-negative or sero-positive patients). Plasmapheresis or IVIG is the treatment for exacerbations. Their main advantage is the rapid onset of the effect; 3 to 5 PE or IVIG infusions (1.2 to 2 g/body weight administered over 2 to 5 days) are usually recommended. In case of suspected thymoma, thymectomy should be always performed. The option of thymectomy was discussed in young patients less than 50 years old with unstable MG, even if thymoma lesions are not suspected. Corticosteroids and/or immunosuppressive agents are used in severe forms of the disease. A few randomized studies have shown the effectiveness of the therapeutic agents. Corticosteroids are considered a major treatment of MG but the doses and periods of time are still being debated. The combination of corticosteroids and immunosuppressive agents are recommended early to spare corticosteroids. The treatment of MG should be modulated regularly (minimal doses for example). The use of IVIG prior to thymectomy was not discussed.
The European Federation of Neurological Societies' task force on the use of IVIG in treatment of neurological diseases (Elovaara et al, 2008) stated that IVIG is an effective treatment for acute exacerbations of MG and for short-term treatment of severe MG (level A); and IVIG is similar to PE regarding effect. This treatment is safe also for children, during pregnancy, and for elderly patients with complicating disorders. There is not sufficient evidence to recommend IVIG for chronic maintenance therapy in MG alone or in combination with other immunoactive drugs. Furthermore, the use of IVIG before thymectomy was not discussed.
Morozumi and associates (2009) evaluated the effect of IVIG therapy in the treatment of neuropathic pain associated with Sjogren's syndrome. These investigators examined 5 patients affected by painful sensory neuropathy associated with Sjögren's syndrome. All patients were treated with IVIG (0.4 g/kg/day for 5 days) and pain rating was assessed by the visual analog scale (VAS). All 5 patients showed a remarkable improvement in neuropathic pain following IVIG therapy. Pain, assessed by the determination of mean VAS score, was reduced by 73.4 % from days 2 to 14 following treatment. The observed clinical improvement persisted for 2 to 6 months. One patient, examined by quantitative sensory testing, showed an improvement of superficial sensory deficit accompanied by pain relief. The authors concluded that IVIG might be an effective treatment for pain in Sjögren's syndrome-associated neuropathy. They stated that further studies should be done in a controlled, blind study.
Ishii et al (1994) examined the clinical effects of PE and high dose IVIG in a 41-year old woman with Isaacs' syndrome. After double filtration PE, symptoms almost disappeared for 2 to 3 weeks and the recorded continuous muscle action potentials were considerably decreased. Symptoms recurred within a few months. On the other hand, IVIG worsened the symptoms of the disorder: during and after IVIG at a dose of 0.2 g/kg/day (total 50 g), widespread myokymia, pseudomyotonia, and muscle cramps gradually increased. Symptoms improved after another course of PE.
Myers and Baker (2009) noted that acquired neuromyotonia, also known as Isaacs' syndrome, has been described in combination with a variety of other autoimmune disorders; however there has never been a report of sero-positive Isaacs' syndrome in a patient with a history of Guillain-Barre syndrome (GBS). Both conditions involve antibody-mediated autoimmune effects on the peripheral nervous system, although the clinical manifestations are quite different. These researchers presented a man who experienced an episode of GBS at the age of 21 and subsequently developed Isaacs' syndrome at the age of 24 which was positive for anti-voltage-gated potassium channel (VGKC) antibodies. When treated with IVIG, he developed an eczematous rash that differed markedly in pattern and duration from the usual presentation for this IVIG reaction.
Aries and colleagues (2005) stated that initially IVIGs were used as replacement therapy in primary and secondary antibody-deficiency syndromes. The clinical use of IVIG has been extended during the past decade to a wide variety of clinical conditions, such as infectious processes, neuroimmunological diseases, and different systemic autoimmune diseases. The mode of action of IVIG is complex, involving modulation of the Fc receptors, interference with the complement and cytokine network, and effects on the activation and differentiation of T and B-cells. Kawasaki disease (KD) was one of the first diseases within the group of primary vasculitides in which IVIG were used. Today, there is a clear evidence of benefit for IVIG in the treatment of coronary artery abnormalities related to KD. Subsequently, various reports have suggested a beneficial effect in other vasculitides; however, there are few data from controlled studies. For anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), 1 placebo-controlled and several open-label studies have shown a beneficial effect on the disease activity in patients with Wegener's granulomatosis or microscopic polyangiitis refractory to standard therapy with prednisone and cyclophosphamide. For other vasculitides, such as polyarteritis nodosa or Henoch-Schonlein purpura, only case reports have described an inhibition of a disease progression by IVIG so far. However, the effect was partly only temporary. The authors concluded that KD and AAV are the only vasculitides with a definite beneficial use of IVIG. For other vasculitides, the efficacy of IVIG has not been proven properly but may be useful in single cases.
Eleftheriou and Brogan (2009) stated that primary systemic vasculitides of the young are relatively rare diseases, but can have a significant morbidity and mortality. The purpose of this review was to provide an overview of the pediatric vasculitides. Vasculitides that predominantly affect children will be considered in more detail than vasculitic diseases that although are seen in children affect adults more commonly, such as the ANCA associated vasculitides. New classification criteria for childhood vasculitis have recently been proposed and are currently undergoing validation. Epidemiological clues continue to implicate infectious triggers in KD and Henoch Schönlein purpura. Several genetic polymorphisms have now been described in the vasculitides that may be relevant in terms of disease predisposition or development of disease complications. Treatment regimens continue to improve, with the use of different immunosuppressive medications and newer therapeutic approaches such as biologic agents. However new challenges are looming in regards to the role of inflammation in endothelial health and the long term cardiovascular morbidity for children with primary systemic vasculitis. International multi-center collaboration is of utmost importance in order for us to further advance the understanding and improve the treatment and outcome of systemic vasculitis in the young. Furthermore, an UpToDate review on "IgA vasculitis (Henoch-Schönlein purpura): Management" (Dedeoglu and Kim, 2021) did not mention the use of IVIG as a therapeutic option.
Ishii and associates (2010) stated that treatment of autoimmune bullous skin diseases can often be challenging and primarily consists of systemic corticosteroids and a variety of immunosuppressants. Current treatment strategies are effective in most cases but hampered by the side effects of long-term immunosuppressive treatment. I ntravenous immunoglobulin is one potential promising therapy for patients with autoimmune bullous skin diseases, and evidence of its effectiveness and safety is increasing. A number of autoimmune bullous skin diseases have been identified in which IVIG treatment may be beneficial. However, experience with IVIG in patients with autoimmune skin blistering disease is limited, where it is recommended for patients not responding to conventional therapy. The mode of action of IVIG in autoimmune diseases, including bullous diseases is far from being completely understood. These researchers summarized the clinical evidence supporting the notion, that IVIG is a promising therapeutic agent for the treatment of patients with autoimmune bullous skin disease. In addition, they reviewed the proposed modes of action. In the future, randomized controlled trials are necessary to better determine the efficacy and adverse effects of IVIG in the treatment of autoimmune bullous skin diseases.
Jolles (2011) noted that high-dose IVIG (hdIVIG) is being used increasingly for dermatological indications. Its mode of action is via a number of proposed mechanisms and it is not associated with the many side-effects of steroids and other immunosuppressive agents. The evidence for using hdIVIG in the treatment of autoimmune bullous disorders is based on uncontrolled trials and case reports. However, there are now 62 reported patients and this review aimed to make a critical assessment of the current data. This has been obtained from a Medline search of the English literature from 1966 to 2000 for pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, pemphigoid gestationis, cicatricial pemphigoid, epidermolysis bullosa acquisita and linear IgA disease. Taken together hdIVIG was effective in 81 % of the patients with blistering disease. Patients appear to be more likely to respond when hdIVIG is used as adjunctive therapy (91 % response rate) than as monotherapy (56 % response rate). The authors concluded that hdIVIG may offer a safe potential therapeutic avenue for resistant cases of the autoimmune bullous disorders but should be further assessed using double-blind placebo-controlled trials.
Parambil et al (2011) stated that small fiber neuropathy (SFN) is commonly associated with sarcoidosis and can cause significant morbidity to afflicted patients. The appropriate treatment of this condition, when associated with sarcoidosis, is not well established. These investigators described case series of 3 patients with sarcoidosis and SFN; the presenting clinical features, skin biopsy results, autonomic reflex screen and quantitative sudomotor axon reflex testing (QSART) findings, and response to therapy were delineated. They described 3 patients with biopsy-proven sarcoidosis who developed intractable neuropathic pain and/or symptoms related to associated autonomic dysfunction despite treatment with various immunosuppressive medications and narcotic analgesics. QSART showed evidence of a post-ganglionic sudomotor abnormality in 1 patient and was normal in the other 2. Skin biopsy findings were abnormal, demonstrating a non-length-dependent sensory SFN in all 3 patients. Painful neuropathic symptoms, as well as symptoms related to dysautonomia from SFN responded significantly to treatment with IVIG. The authors concluded that IVIG appears to be effective in relieving symptoms from SFN associated with sarcoidosis, suggesting an underlying immune mechanism. Moreover, they stated that larger prospective, controlled studies are needed to confirm this response to IVIG and to further elucidate the underlying pathobiology behind this association with sarcoidosis.
Isobe et al (2004) described the case of a 40-year old female diagnosed with follicular lymphoma who was treated with rituximab-combined chemotherapy. Although she achieved complete remission, she developed progressive anemia and reticulocytopenia. Bone marrow examination revealed features of pure red cell aplasia and hemophagocytosis. In addition, the appearance of large pronormoblasts suggested that she was infected with parvovirus B19. Excess viral DNA in her bone marrow confirmed that her illness was caused by persistent parvovirus B19 infection. Serum immunoglobulin levels decreased beyond the lower normal limit, which indicated that her humoral immunity was impaired after rituximab-combined chemotherapy. Although she had been infected with parvovirus B19, she was re-infected and failed to control the viral expansion. High-titer immunoglobulin against parvovirus B19 was intravenously administrated and resulted in remarkable reticulocytosis and improvement of anemia. High-titer immunoglobulin, which contained a sufficient amount of neutralizing antibodies against parvovirus B19, likely inactivated most viruses in vivo. These investigators successfully eradicated the virus after 2 courses of high-dose therapy at 0.5 g/kg/day every week followed by 8 courses of maintenance therapy at 0.1 g/kg/day every other week. It is important to consider that parvovirus B19 infection is a possible cause of progressive anemia in B-cell lymphoma patients treated with rituximab-combined chemotherapy. The authors proposed that the use of high-titer immunoglobulin against parvovirus B19 may enable such immunocompromised patients to eradicate the virus before sufficient immune system reconstruction. Also, UpToDate reviews on "Initial treatment of stage I follicular lymphoma" (Freedman, Friedberg, and Ng, 2021) and "Treatment of relapsed or refractory follicular lymphoma" (Freedman and Friedberg, 2021) do not mention the use of IVIG.
Perlmutter et al (1999) examined if plasma exchange or IVIG would be better than placebo (sham IVIG) in reducing severity of neuropsychiatric symptoms in children, exacerbations of tics and obsessive symptoms. Children with severe, infection-triggered exacerbations of obsessive-compulsive disorder (OCD) or tic disorders, including Tourette syndrome, were randomly assigned treatment with plasma exchange (5 single-volume exchanges over 2 weeks), IVIG (1 g/kg daily on 2 consecutive days), or placebo (saline solution given in the same manner as IVIG). Symptom severity was rated at baseline, and at 1 month and 12 months after treatment by use of standard assessment scales for OCD, tics, anxiety, depression, and global function. A total of 30 children entered the study and 29 completed the trial. Ten received plasma exchange, 9 IVIG, and 10 placebo. At 1 month, the IVIG and plasma exchange groups showed striking improvements in obsessive-compulsive symptoms (mean improvement on children's Yale-Brown obsessive compulsive scale score of 12 [45 %] and 13 [58 %], respectively), anxiety (2.1 [31 %] and 3.0 [47 %] improvement on National Institute of Mental Health anxiety scale), and overall functioning (2.9 [33 %] and 2.8 [35 %] improvement on National Institute of Mental Health global scale). Tic symptoms were also significantly improved by plasma exchange (mean change on Tourette syndrome unified rating scale of 49 %). Treatment gains were maintained at 1 year, with 14 (82 %) of 17 children "much" or "very much" improved over baseline (7 of 8 for plasma exchange, 7 of 9 for IVIG). The authors concluded that plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection-triggered OCD and tic disorders. They stated that further studies are needed to determine the active mechanism of these interventions, and to determine which children with OCD and tic disorders will benefit from immunomodulatory therapies.
In a double-blind placebo-controlled study, Hoekstra et al (2004) studied the effects of IVIG on tics. A total of 30 patients with a DSM-IV tic disorder were randomly assigned to IVIG (1 g/kg on 2 consecutive days; mean age = 28.71 years; range of 14 to 53 years) or placebo (mean age = 30.73 years; range of 14 to 63 years). Symptoms were rated with the Yale Global Tic Severity Scale, the Yale-Brown Obsessive Compulsive Scale, and the Clinical Global Impressions scale of symptom change with regard to tic severity. These were used at baseline and on weeks 2, 4, 6, 10, and 14 post-treatment, after which blinding was broken. The study was conducted from March through August 2002. These researchers observed no significant differences between both treatment groups regarding post-treatment changes in tic severity. Severity of obsessions and compulsions, which was in the subclinical range, decreased significantly in the IVIG group compared with the placebo group at week 6 (p = 0.02). Then, there was a 32.3 % improvement in the IVIG group compared with baseline. Though this improvement was maintained over the following 8 weeks, no statistically significant differences between the IVIG and the placebo group with regard to improvements in obsessions and compulsions were detected at subsequent assessments. IVIG treatment was associated with significantly more side effects than placebo, most notably headache. The authors concluded that based on the present results, IVIG can not be recommended in tic disorders.
Trucco et al (2011) evaluated the outcome of maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis following IVIG and corticosteroid therapy. These researchers have previously shown that 85 % of fetuses and infants with maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis suffer demise or need for transplant. In an attempt to improve this outcome, in 1998, they began to empirically treat affected patients with IVIG and corticosteroids. These investigators reviewed the clinical records and echocardiograms of 20 affected patients encountered in their institutions and treated with IVIG and corticosteroids from 1998 to 2009. All 20 were initially referred at a median gestational age of 23 weeks (range of 18 to 38 weeks); 19 mothers were anti-Ro antibody positive, 8 anti-La antibody positive, and 7 had clinical autoimmune disease. Endocardial fibroelastosis was seen in 16 and was not obvious in 4 others with reduced ventricular function, and 16 (80 %) had reduced or borderline ventricular shortening fraction (less than or equal to 30 %) before or after birth. Eighteen had atrioventricular block at referral (16 in 3°). During pregnancy, maternal IVIG was given in 9 and dexamethasone in 17. After birth, 17 infants received IVIG (n = 14) and/or corticosteroids (n = 15). Twelve underwent pacemaker implantation. Four with hydrops at presentation died perinatally, despite initial improvement in function in 3. At a median follow-up of 2.9 years (1.1 to 9.8 years), 16 (80 %) patients are currently alive with normal systolic ventricular function and 6 are not paced. The authors concluded that treatment of maternal autoantibody-mediated fetal cardiomyopathy/endocardial fibroelastosis with IVIG and corticosteroids potentially improves the outcome of affected fetuses. They stated that further studies (prospective, multi-center randomized trials including the evaluation of maternal and neonatal titers before and after therapy) are needed to determine the optimal dose and timing of IVIG administration.
In a Cochrane review, Ohlsson et al (2010) evaluated the effect of IVIG on mortality/morbidity caused by suspected infection in neonates and in those neonates who had suspected infection on study entry and later were confirmed as being infected. These investigators searched MEDLINE, EMBASE, The Cochrane Library, the reference lists of identified studies, meta-analyses and personal files in December 2009. They selected randomized or quasi-randomized controlled trials of IVIG for the treatment of suspected bacterial/fungal infection compared to placebo or no intervention in newborn infants (less than 28 days old). Statistical analyses included Typical Relative Risk (RR), Risk Difference (RD), weighted mean difference (WMD), the number needed to treat to benefit (NNTB) (all with with 95 % CI and the I(2) statistic to examine statistical heterogeneity. The updated search identified 1 new study; 10 studies of variable quality undertaken in 8 countries are included in this review. Mortality in infants with clinically suspected infection was reduced following IVIG treatment [7 studies (n = 378); typical RR 0.58 (95 % CI: 0.38, 0.89); typical RD -0.10 (95 % CI: - 0.18, -0.03); NNTB 10 (95 % CI: 6, 33); I(2) = 0 %]. Mortality in cases of subsequently proven infection was reduced [7 trials (n = 262); typical RR 0.55 (95 % CI: 0.31, 0.98); I(2) = 0 %]. The authors concluded that because of concerns about study quality, there is still insufficient evidence to support the routine administration of IVIG to prevent mortality in infants with suspected or subsequently proved neonatal infection. A large study of the effectiveness of IVIG in neonates with suspected infection has recently been completed. Results of the International Neonatal Immunotherapy Study (INIS trial), which enrolled 3,493 infants, are expected to be published in 2010. The results of that trial should establish the usefulness of IVIG for suspected infection in newborns.
The INIS Collaborative Group (2011) stated that neonatal sepsis is a major cause of death and complications despite antibiotic treatment. Effective adjunctive treatments are needed. Newborn infants are relatively deficient in endogenous immunoglobulin. Meta-analyses of trials of IVIG for suspected or proven neonatal sepsis suggest a reduced rate of death from any cause, but the trials have been small and have varied in quality. At 113 hospitals in 9 countries, these investigators enrolled 3,493 infants receiving antibiotics for suspected or proven serious infection and randomly assigned them to receive 2 infusions of either polyvalent IgG immune globulin (at a dose of 500 mg/kg body weight) or matching placebo 48 hours apart. The primary outcome was death or major disability at the age of 2 years. There was no significant between-group difference in the rates of the primary outcome, which occurred in 686 of 1,759 infants (39.0 %) who received IVIG and in 677 of 1,734 infants (39.0 %) who received placebo (relative risk, 1.00; 95 % CI: 0.92 to 1.08). Similarly, there were no significant differences in the rates of secondary outcomes, including the incidence of subsequent sepsis episodes. In follow-up of 2-year-old infants, there were no significant differences in the rates of major or non-major disability or of adverse events. The authors concluded that therapy with IVIG had no effect on the outcomes of suspected or proven neonatal sepsis.
Kim and colleagues (2011) stated that the prognosis of MG has improved dramatically due to advances in critical-care medicine and symptomatic treatments. Its immunopathogenesis is fundamentally a T-cell-dependent autoimmune process resulting from loss of tolerance toward self-antigens in the thymus. Thymectomy is based on this immunological background. For MG patients who are inadequately controlled with sufficient symptomatic treatment or fail to achieve remission after thymectomy, remission is usually achieved through the addition of other immunotherapies. These immunotherapies can be classified into 2 groups:- rapid induction and
- long-term maintenance.
Rapid induction therapy includes IVIG and PE. These produce improvement within a few days after initiation, and so are useful for acute exacerbation including myasthenic crisis or in the peri-operative period. High-dose prednisone has been more universally preferred for remission induction, but it acts more slowly than IVIG and PE, commonly only after a delay of several weeks. Slow tapering of steroids after a high-dose pulse offers a method of maintaining the state of remission. However, because of significant side effects, other immunosuppressants (ISs) are frequently added as "steroid-sparing agents". The currently available ISs exert their immunosuppressive effects by 3 mechanisms:
- blocking the synthesis of DNA and RNA,
- inhibiting T-cell activation and
- depleting the B-cell population.
In addition, newer drugs including antisense molecule, tumor necrosis factor alpha receptor blocker and complement inhibitors are currently under investigation to confirm their effectiveness. Until now, the treatment of MG has been based primarily on experience rather than gold-standard evidence from randomized controlled trials. It is hoped that well-organized studies and newer experimental trials will lead to improved treatments.
A review of treatment of IgG subclass deficiencies (Knutsen, 2021) explains that, "in patients receiving immune globulin replacement therapy, treatment should periodically be held after one to two years for immunologic and clinical reassessment. When discontinuing immune globulin, it is advisable to do so during the spring months to minimize exposure to viral infections. We generally wait three or four months after discontinuation before performing immune testing." The authors explain, as a rationale for this reassessment, that some people do not respond to IgG replacement therapy, and also that, especially in younger patients, immune responsiveness and IgG subclass levels may normalize over time.
The American College of Obstetricians and Gynecologists’ practice bulletin on "Antiphospholipid syndrome" (ACOG, 2011) indicated that IVIG was considered but not recommended for pregnant women with APS.
Also, the British Committee for Standards in Haematology’s guidelines on "The investigation and management of antiphospholipid syndrome" (Keeling et al, 2012) does not mention the use of IVIG.
Alijotas-Reig (2013) stated that currently there are no reliable data regarding the actual treatment received by women with refractory obstetric APS (OAPS). These researchers evaluated current clinical evidence and new trends in the treatment of refractory OAPS. A non-systematic but comprehensive literature search using relevant keywords was made to identify relevant articles published in English from different computerized databases: PubMed (Medline), Google Scholar electronic database search and The Cochrane Library, from January 2000 to March 2012. Studies on the treatment of poor obstetric outcomes in women with OAPS were included. Prospective randomized clinical trials, cohort studies, reviews, systematic reviews and meta-analysis were retrieved. A total of 130 articles were finally selected for this review, including 17 randomized clinical trials and 4 meta-analyses. The majority of articles were non-randomized original papers and basic and clinical reviews. The authors concluded that up to 20 % of women with OAPS do not receive the currently recommended therapeutic regimen. Unfortunately, well-designed studies regarding the usefulness of new drugs in refractory OAPS are scarce. Hydroxychloroquine and low-dose prednisolone appear to be useful when added to standard therapy. Current data do not support the use of IVIG in this field.
The American Academy of Child and Adolescent Psychiatry’s practice parameter for the assessment and treatment of children and adolescents with obsessive-compulsive disorder (AACAP, 2012) stated that "Therapeutic plasma exchange and intravenous immunoglobulin remain experimental interventions with substantial risk and potential morbidity".
Also, UpToDate reviews on "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis" (Krull, 2020), and "Treatment of attention deficit hyperactivity disorder in adults" (Brent, Bukstein, and Solanto, 2020) do NOT mention the use of IVIG as a therapeutic option.
An UpToDate review on "The diffuse alveolar hemorrhage syndromes" (King, 2021) states that "The possible role of intravenous immunoglobulin (IVIG) in patients with DAH due to vasculitis or other rheumatic disease is unknown".
Perlmutter et al (1999) reported on 29 children who were randomized to one of three groups: plasma exchange (n = 10), IVIG (n = 9), or placebo (n = 10). They found that at 1 month, the IVIG and plasma-exchange groups showed striking improvements in obsessive-compulsive symptoms (mean improvement on children’s Yale-Brown obsessive compulsive scale score of 12 [45 %] and 13 [58 %], respectively), anxiety (2·1 [31 %] and 3·0 [47 %] improvement on National Institute of Mental Health anxiety scale), and overall functioning (2·9 [33 %] and 2·8 [35 %] improvement on National Institute of Mental Health global scale). The investigators concluded that plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection triggered OCD and tic disorders. The investigators stated that further studies are needed to determine the active mechanism of these interventions, and to determine which children with OCD and tic disorders will benefit from immunomodulatory therapies. This 3- armed trial with 10 or less participants per arm has limited statistical power.
The AAN’s evidence-based guideline on "Intravenous immunoglobulin in the treatment of neuromuscular disorders" (Patwa et al, 2012) states that IVIG is as efficacious as plasmapheresis and should be offered for treating Guillain-Barré syndrome (GBS) in adults (Level A). IVIG is effective and should be offered in the long-term treatment of chronic inflammatory demyelinating polyneuropathy (Level A). IVIG is probably effective and should be considered for treating moderate-to-severe myasthenia gravis and multifocal motor neuropathy (Level B). IVIG is possibly effective and may be considered for treating non-responsive dermatomyositis in adults and Lambert-Eaton myasthenic syndrome (Level C). Evidence is insufficient to support or refute use of IVIG in the treatment of immunoglobulin M paraprotein-associated neuropathy, inclusion body myositis, polymyositis, diabetic radiculoplexoneuropathy, or Miller Fisher syndrome, or in the routine treatment of post-polio syndrome or in children with GBS (Level U). IVIG combined with plasmapheresis should not be considered for treating GBS (Level B). More data are needed regarding IVIG efficacy as compared with other treatments/treatment combinations.
In a Cochrane review, Gajdos et al (2012) examined the effectiveness of IVIG for treating exacerbations of MG or for chronic MG. These investigators searched the Cochrane Neuromuscular Disease Group Specialized Register (October 11, 2011), CENTRAL (2011, Issue 3), MEDLINE (January 1966 to September 2011) and EMBASE (January 1980 to September 2011) using 'myasthenia gravis' and 'intravenous immunoglobulin' as the search terms. All randomized controlled trials (RCTs) or quasi-RCTs in which IVIG was compared with no treatment, placebo or plasma exchange, in people with MG. One review author extracted the data and 2 others checked these data. For methodological reasons, no formal meta-analysis was performed. These researchers identified 7 RCTs. These trials differ in inclusion criteria, comparison with alternative treatment and outcomes. In a trial comparing IVIG with placebo, including 51 participants with MG worsening, the mean difference (MD) in quantitative MG score (QMGS) (MD 95 % CI) after 14 days was: -1.60 (95 % CI: - 3.23 to 0.03) this result being borderline statistically significant in favor of IVIG. In an unblinded study of 87 participants with exacerbation comparing IVIG and PE there was no difference in myasthenic muscle score (MMS) after 15 days (MD -1.00; 95 % CI: -7.72 to 5.72). In a study of 84 participants with worsening MG there was no difference in change in QMGS 14 days after IVIG or PE (MD -1.50; 95 % CI: -3.43 to 0.43). In a study of 12 participants with moderate or severe MG, which was at high-risk of bias from skewed allocation, the mean fall in QMGS both for IVIG and PE after 4 weeks was significant (p < 0.05). A study with 15 participants with mild or moderate MG found no difference in change in QMGS 42 days after IVIG or placebo (MD 1.60; 95 % CI: -1.92 to 5.12). A study included 33 participants with moderate exacerbations of MG and showed no difference in change in QMGS 14 days after IVIG or methylprednisolone (MD -0.42; 95 % CI: -1.20 to 0.36). All these 3 smaller studies were under-powered. The last trial, including 168 people with exacerbations, showed no evidence of superiority of IVIG 2 g/kg over IVIG 1 g/kg on the change of MMS after 15 days (MD 3.84; 95 % CI: -0.98 to 8.66). Adverse events due to IVIG were moderate (fever, nausea, headache), self-limiting and subjectively less severe than with PE (although, given the available data, no statistical comparison was possible). Other than where specific limitations were mentioned the trials were generally at low-risk of bias. The authors concluded that in exacerbation of MG, 1 RCT of IVIG versus placebo showed some evidence of the efficacy of IVIG and 2 did not show a significant difference between IVIG and PE. Another showed no significant difference in efficacy between 1 g/kg and 2 g/kg of IVIG. A further, but under-powered, trial showed no significant difference between IVIG and oral methylprednisolone. They stated that in chronic MG, there is insufficient evidence from RCTs to determine whether IVIG is effective.
The Ad Hoc Committee of the Croatian Society for Neurovascular Disorders/Croatian Medical Association’s guidelines for the use of IVIG in the treatment of neurologic diseases (Bascic-Kes et al, 2012) stated that the use of IVIG in the management of patients with neuroimmune disorders has shown a progressive trend over the last few years. Despite the wide use of IVIG, consensus on its optimal use is deficient. The European Federation of Neurological Societies (EFNS) guidance regulations offered consensus recommendations for optimal use of IVIG. The effectiveness of IVIG has been proven in Guillain-Barre syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multi-focal mononeuropathy (level A), acute exacerbations of MG and short-term treatment of severe MG (level A). As a second-line treatment, the use of IVIG is recommended in dermatomyositis in combination with prednisone (level B) and is considered as a treatment option in polymyositis (level C). As a 2nd- or even 3rd-line therapy, the use of IVIG should be considered in patients with RRMS if conventional immunomodulatory therapies are not tolerated (level B) and in relapses during pregnancy or post-partum period (good clinical practice point). Finally, it appears that the use of IVIG has a beneficial effect also in stiff-person syndrome (level A), some paraneoplastic neuropathies (level B), and some acute-demyelinating diseases and childhood refractory epilepsy (good practice point). The guideline did not mention the use of IVIG as a maintenance therapy for MG.
In a Cochrane review, Lunn and Nobile-Orazio (2012) evaluated the effects of immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated demyelinating peripheral neuropathy. These investigators searched the Cochrane Neuromuscular Disease Group Specialized Register June 6, 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to May 2011) and EMBASE (January 1980 to May 2011) for controlled trials. They also checked bibliographies and contacted authors and experts in the field. These researchers included randomized or quasi-randomized controlled trials involving participants of any age treated with any type of immunotherapy for anti-myelin-associated glycoprotein antibody-associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance and of any severity. The primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin Scale at 6 months after randomization. Secondary outcome measures were: Neuropathy Impairment Scale or the Modified Rankin Score at 12 months after randomization; 10-meter walk time, subjective clinical scores and electrophysiological parameters at 6 and 12 months after randomization; IgM paraprotein levels and anti-myelin-associated glycoprotein antibody titers at 6 months after randomization; and adverse effects of treatments. The 2 authors independently selected studies; and 2 authors independently assessed the risk of bias in included studies. These investigators identified 7 eligible trials (182 participants), which tested IVIG, alfa-interferon alfa-2a, PE, cyclophosphamide and steroids, and rituximab. Only 2 trials, of IVIG (with 33 participants, including 20 with antibodies against myelin-associated glycoprotein), had comparable interventions and outcomes, but both were short-term trials. There were no clinical or statistically significant benefits of the treatments used on the outcomes pre-defined for this review, but not all the predefined outcomes were used in every included trial. Intravenous immunoglobulin showed a statistical benefit in terms of improvement in Modified Rankin Scale at 2 weeks and 10-meter walk time at 4 weeks. Cyclophosphamide failed to show any benefit in the trial's primary outcome, and showed a barely significant benefit in the primary outcome specified here, but some toxic adverse events were identified. A trial of rituximab was of poor methodological quality with a high risk of bias and a further larger study is awaited. Serious adverse events were few in the other trials. The authors concluded that there is inadequate reliable evidence from trials of immunotherapies in anti-myelin-associated glycoprotein paraproteinemic neuropathy to form an evidence base supporting any particular immunotherapy treatment. There is very low quality evidence of benefit from rituximab. They stated that large, well-designed, randomized trials of at least 6 to 12 months duration are needed to evaluate existing or novel therapies, preferably employing unified, consistent, well-designed, responsive and valid outcome measures.
Furthermore, in a review on "Intravenous immunoglobulin for treatment of neuromuscular disease", Ruzhansky and Brannagan (2013) stated that "Clinical trials in amyotrophic lateral sclerosis, inclusion body myositis, and anti–myelin-associated glycoprotein neuropathy have been negative".
Drulovic et al (2011) noted that Hashimoto's encephalopathy (HE) is a rare autoimmune syndrome characterized by various neuropsychiatric manifestations, responsive to steroid treatment and associated with Hashimoto's thyroiditis. There are only a few reports suggesting that IVIG might represent an effective treatment modality for the severe steroid-resistant HE cases. These investigators presented a patient with HE who developed a complete recovery after the IVIG therapy followed by a long-lasting remission. After detailed examinations, the diagnosis of HE was established. Two years later, in June 2001, new manifestations (unsteadiness in gait, personality changes, seizures, and persistent headache) gradually developed during a 6-month period. Response to steroids was unsatisfactory and partial, since headaches and personality changes had continuously worsened. In January 2002, the patient received IVIG (0.4 g/kg body weight daily for 5 days). Gradual improvement was noticed and a complete recovery developed over the following weeks. Up to March 2009, during a 7-year follow-up period, remission persisted. The authors concluded that to their best knowledge, this was the first report of a long-lasting remission of HE after IVIG therapy. Therefore, this case further supported administration of IVIG, as a potentially beneficial treatment modality, in severe cases of HE that are completely or partially resistant to steroids.
Olmez et al (2013) shared their experience on clinical presentation and management of patients diagnosed with HE. These researchers identified 13 patients who met the criteria for the diagnosis of HE. The median age was 49 years (range of 2 to 66) and all except 1 were women. Encephalopathy in the form of altered mental status, stroke-like symptoms or seizures, with prompt resolution of symptoms upon receiving steroids, was the commonest presentation, seen in 7 patients. The second commonest presentation was subacute progressive decrease in cognitive function, which reversed within days to weeks after steroid therapy, seen in 4 patients. Electroencephalogram (EEG) was available in 12 patients and was abnormal in 8, showing non-specific cerebral dysfunction in all 8 and epileptiform activity in 3. Treatment consisted of steroids in the acute phase for 12 of 13 patients with rapid improvement in symptoms. Maintenance therapy was rituximab in 7 patients, IVIG in 7, azathioprine in 4, mycophenolate mofetil in 3, and methotrexate in 1 (some patients received sequential therapy with different agents). There was complete or near complete resolution of symptoms in 12 of the 13 patients. The authors concluded that they presented a cohort of patients in whom central nervous system dysfunction was associated with elevated anti-thyroid antibodies and reversal of disease followed immunomodulatory therapies. This was a small study and the findings were confounded by sequential therapies with different agents.
He and colleagues (2013) reported the findings of a case of a 61-year old man presented with unconsciousness, spasms and a previous misdiagnosis as viral encephalitis. Response to anti-viral and steroid therapy was unsatisfactory, but treatment with immunoglobulin combined with corticosteroid therapy achieved rapid and complete recovery. The authors concluded that any patient presenting with acute or subacute unexplained encephalopathy should be considered HE, even if the thyroid function is normal. Thyroid antibody testing should be performed because this may be the most important clue to diagnosis. As soon as the diagnosis is made, steroid therapy is the first choice. If the steroid therapy does not lead to immediate improvement, IVIG is an effective alternative treatment.
An UpToDate review on "Hashimoto encephalopathy" (Rubin, 2021) stated that "Clinical improvement with intravenous immunoglobulin, and plasmapheresis has been reported in individual cases". However, IVIG is not mentioned in the "Summary and Recommendations" of this review.
Since available evidence is based on single-case studies as well as small case-series studies, the role of IVIG for the treatment for autoimmune encephalopathy has yet to be established.
In a Cochrane review, Wong et al (2013) assessed the safety and effectiveness of the use of IVIG antenatally to women with severe fetal red blood cell alloimmunization. These investigators searched the Cochrane Pregnancy and Childbirth Group trials register (December 19, 2012), and reference lists of articles. Randomized trials assessing the antenatal use of IVIG administered at any dose, frequency or duration with a control group (using any other, or no treatment) in the management of fetal red blood cell alloimmunization were selected for analysis. Two review authors independently assessed the available evidence. There were no included studies. The authors concluded that no information is available from randomized trials to indicate whether the antenatal use of IVIG is effective in the management of fetal red blood cell alloimmunization. Several case series suggested a beneficial role in delaying the onset of fetal anemia requiring invasive intrauterine transfusion.
An UpToDate review on "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention" (Modlin, 2021) stated that "The therapeutic options for serious enterovirus infections are limited. Intravenous immunoglobulin (IVIG) is often administered despite a lack of convincing evidence for efficacy, and in the United States, Food and Drug Administration-approved antiviral drugs are not available. We do not routinely administer IVIG for severe enterovirus infections. However, for patients with life-threatening infections, including neonatal infection, myocarditis, chronic infection in B-cell immunodeficiency, and disseminated infections in persons with hematologic malignancies, it is reasonable to administer IVIG and to explore whether an experimental antiviral drug or drugs are available under a treatment investigational new drug (IND) application."
Joao (2007) stated that human B cell immune deficiencies are associated with increased susceptibility to viral and fungi infections, which are T cell immunity related infections. Also, some viral infections occurring in immune depressed patients such as cytomegalovirus (CMV) infections are recommended to be treated with IVIG in combination with anti-viral therapy. This fact has no clear biological explanation but it has been shown to be successful. Recently, B cells and immunoglobulin were identified as essential elements driving T cell receptor (TCR) diversity generation. Idiotype peptides of B cell immunoglobulin may be the driving force for the antigen presenting function of B cells and other antigen presenting cells to influence the T cell repertoire. This seems to be another relevance of Jerne's idiotypic network and another function of immunoglobulin. Since T cells function depends on the diversity of the TCR repertoire, means to increase the diversity of the T cell repertoire may improve T cell function in situations characterized by a contracted TCR repertoire (e.g., AIDS, primary immunodeficiency, cancer, autoimmunity and following chemotherapy and hematopoietic precursors transplantation). The clinical hypothesis put forth by this researcher is that B cells and/or immunoglobulin may be used therapeutically aiming to increase and potentially to restore T cell repertoire diversity improving T cell function in situations implicating a contracted T cell repertoire. The fact that immunoglobulin influences the composition of T cell repertoire by increasing its diversity allows a much wider application of this molecule in the clinical practice. The author presented a novel reasoning for the use of IVIG in humans, which should be explored. All the situations where immune reconstitution occurs are potentially a target for this therapeutically mechanism, aiming to improve the diversity of the reconstituted immune repertoires. This new role of Ig molecule may help to explain several effects that IVIG have in the T cell compartment, such as modulation of the activation and function of effectors T cells. The idea that immunoglobulin is essential in the generation and maintenance of a diverse compartment of T cells, affecting T cell function via that mechanism suggests a promising approach to medical conditions involving immune reconstitution. Furthermore, it represents a new paradigm of understanding the immune system as a complex, interdependent web of cells/cell products that inter-affect each other generation, function and survival.
Schmidt-Hieber et al (2009) developed a novel algorithm to define the need for high-dose prophylactic IVIG in periods of high-risk for CMV to patients after allo-SCT. Intravenous immunoglobulins were administered only if at least one of the following, monthly-assessed, criteria was fulfilled:- IgG concentration less than 4 g/L,
- NK (natural killer) cell count less than 100/microl,
- CD4(+) cell count less than 100/microl, and (iv) acute or chronic GVHD.
The primary end-point was to determine the cumulative incidence of CMV infection in patients who received prophylactic IVIG according to the algorithm (intervention group) and compare it with that of a sequentially assessed control group, to which prophylactic IVIG were not administered. The study included 79 patients (44 in the intervention and 35 in the control group). The estimated cumulative incidence of CMV infection in the intervention and control group did not differ significantly (44 and 36 %; p = 0.31). Additionally, prophylactic IVIG did not reduce the frequency of CMV infection episodes. Cytomegalovirus disease was rare in both cohorts (5 % and 9 %; p = 0.65). The authors concluded that prophylactic IVIG should not be administered after allo-SCT, even if administered selectively in a high-dose to patients with delayed immune reconstitution or GVHD.
Also, an UpToDate review on "Immune reconstitution inflammatory syndrome" (Wolfe 2019) noted that many synonyms exist for IRIS [immune reconstitution inflammatory syndrome]:
- Immune recovery disease
- Immune reconstitution disease
- Immune reconstitution syndrome
- Immune restoration disease
- Immune rebound illness
- Steroid-withdrawal disease
- Immunorestitution disease
- Immune response reactions.
There is no mentioning of IVIG as a therapeutic option for IRIS in this UpToDate review.
Gavhed et al (2011) stated that there is currently no well-accepted therapy for central nervous system Langerhans cell histiocytosis (CNS-LCH), a neuroinflammatory disease clinically characterized by often progressive, neurological symptoms including ataxia, dysarthria, dysphagia, hyper-tonicity, intellectual impairment and behavioral abnormalities. These investigators applied immunomodulative/anti-inflammatory treatment on a patient with progressive CNS-LCH disease – IVIG was administered monthly for 15 years to a patient with severe, image-verified neurodegenerative CNS-LCH. During the IVIG treatment, the neurological deterioration initially appeared to be haltered, but over time there was still some deterioration. The authors concluded that IVIG may be beneficial in partly haltering CNS-LCH neurodegeneration, but further studies are needed.
Edeer-Karaca et al (2010) stated that common variable immunodeficiency (CVID) is an immunodeficiency syndrome characterized by generalized defective antibody production and recurrent sino-pulmonary bacterial infections. Autoimmune disease is common in CVID, occurring in approximately 20 % of patients, with a slight female predominance. Familial inheritance of CVID is very rare, and these investigators reported 2 siblings with CVID presenting remarkable autoimmune manifestations such as relapsing polychondritis, juvenile idiopathic arthritis and chronic inflammatory bowel disease. Autoimmune and inflammatory complications showed minimal improvement under regular IVIG replacement therapy, prophylactic antibiotics and immunosuppressives in these patients.
Also, an UpToDate review on "Treatment of relapsing polychondritis" (Michet, 2020) did not mention IVIG as a therapeutic option.
Hughes et al (2009) noted that idiopathic solar urticaria (SU) is a rare, debilitating photodermatosis, which may be difficult to treat. First-line treatment with anti-histamines is effective in mild cases, but remission after phototherapeutic induction of tolerance is often short-lived. Other treatment options include PE, photopheresis and cyclosporine. These researchers presented 2 cases of severe, idiopathic SU, which were resistant to conventional treatment. Both patients achieved remission after administration of IVIG and have remained in remission at 13 months and 4 years, respectively. There were only 2 case reports of successful treatment of solar urticaria with IVIG. The authors concluded that in their experience IVIG given at a total dose of 2 g/kg over several 5-day courses about a month apart is an effective treatment option for severe idiopathic SU. It is also generally safe, even if certainly subject to significant theoretical risks, such as induction of viral infection or anaphylaxis.
Llamas-Velasco et al (2011) stated that the treatment of SU can be difficult. Only a few cases of SU have been treated with IVIG (as monotherapy or combined with phototherapy), with reported fast and durable increase of solar exposure tolerance. In this study, a 61-year old female with severe UVB- and UVA-induced SU and a 62-year old female with severe UVA and visible light-induced SU were both treated with a single course of IVIG (total dose of 2 g/kg), infused over 3 days. Photo-test, performed 3 months after the treatment, showed only a slight minimal urticating dose improvement, and both patients reported just a moderate and "transient" subjective improvement. The authors concluded that their patients’ poorer response, compared with previous reports, may be due to differences in IVIG treatment schedules.
Adamski et al (2011) reported on the effectiveness of IVIG in severe SU. These researchers performed a retrospective multi-centric study via the mailing of a questionnaire to the French photodermatology units to analyze all cases of patients with SU who were treated with IVIG. A total of 7 patients (5 women) with a mean age of 40 years (range of 32 to 55 years) and a mean disease duration of 5 years (range of 2 to 10 years) received IVIG. The administration schedule differed from one patient to another: 1.4 to 2.5 g/kg were infused over 2 to 5 days. Five of 7 patients obtained a complete remission. The number of courses necessary to obtain clinical remission varied from 1 to 3 courses. Complete remission was maintained during 4 to more than 12 months but anti-histamines were still required. In 1 case, PUVA photochemotherapy was administered. The authors concluded that the findings of this case series suggested a beneficial effect of IVIG in severe SU; but additional prospective trials including a larger number of patients are needed to demonstrate the effectiveness of IVIG and to specify the optimal modalities of their administration in this disease. Drawbacks of this study included its retrospective study design, limited number of patients, and variations in the IVIG administration schedule.
Also, an UpToDate review on "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment" (Elmets, 2021) does not mention the use of IVIG as a therapeutic option.
In a Cochrane review, Ohlsson and Lacy (2013) examined the effects of IVIG on mortality/morbidity caused by suspected or proven infection at study entry in neonates. These researchers also assessed in a subgroup analysis the effects of IgM-enriched IVIG on mortality from suspected infection. MEDLINE, EMBASE, The Cochrane Library, CINAHL, trial registries, Web of Science, reference lists of identified studies, meta-analyses and personal files were searched in 2013. No language restrictions were applied. Randomized or quasi-randomized controlled trials; newborn infants (less than 28 days old); IVIG for treatment of suspected or proven bacterial/fungal infection compared with placebo or no intervention; one of the following outcomes was reported: mortality, length of hospital stay or psychomotor development at follow-up. Statistical analyses included typical risk ratio (RR), risk difference (RD), weighted mean difference (WMD), number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) (all with 95 % CIs and the I-squared (I(2)) statistic to examine for statistical heterogeneity). The updated search identified 1 published study and 1 ongoing study. A total of 8 studies evaluating 3,871 infants were included in this review. Mortality during hospital stay in infants with clinically suspected infection at trial entry was not significantly different after IVIG treatment (8 studies (n = 2,425); typical RR 0.94, 95 % CI: 0.80 to 1.12; typical RD -0.01, 95 % CI: - 0.04 to 0.02 I(2) = 28 % for RR and 32 % for RD). Death or major disability at 2 years corrected age was not significantly different in infants with suspected infection after IVIG treatment (1 study (n = 1,985); RR 0.98, 95 % CI: 0.88 to 1.09 RD -0.01, 95 % CI: -0.05 to 0.03). Mortality during hospital stay was not significantly different after IVIG treatment in infants with proven infection at trial entry (RR 0.95, 95 % CI: 0.74 to 1.21 RD -0.01, 95 % CI: -0.04 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with proven infection at trial entry (RR 1.03, 95 % CI: 0.91 to 1.18; RD 0.01, 95 % CI: -0.04 to 0.06). Mortality during hospital stay in infants with clinically suspected or proven infection at trial entry was not significantly different after IVIG treatment (1 study (n = 3,493); RR 1.00, 95 % CI: 0.86 to 1.16; RD 0.00, 95 % CI: - 0.02 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with suspected or proven infection at trial entry (1 study (n = 3,493); RR 1.00, 95 % CI: 0.92 to 1.09; RD -0.00, 95 % CI: -0.03 to 0.03). Length of hospital stay was not reduced for infants with suspected/proven infection at trial entry (1 study (n = 3,493); mean difference (MD) 0.00 days, 95 % CI: -0.61 to 0.61). No significant difference in mortality during hospital stay after IgM-enriched IVIG treatment for suspected infection was reported at trial entry (3 studies (n = 164); typical RR 0.57, 95 % CI: 0.31 to 1.04; RD -0.12, 95 % CI: -0.24 to 0.00; p = 0.06); I(2) = 2 % for RR and 0 % for RD). The authors concluded that in previous reviews, they encouraged researchers to undertake well-designed trials to confirm or refute the effectiveness of IVIG in reducing adverse outcomes in neonates with suspected infection. Such a trial has been undertaken. Results of the INIS trial, which enrolled 3,493 infants, carried a heavy weight in the current update of this review, and the undisputed results showed no reduction in death or major disability at 2 years of age. They stated that routine administration of IVIG to prevent mortality in infants with suspected or proven neonatal infection is not recommended.
Noguchi et al (2003) reported on the case of a 62-yearold woman who was admitted to the authors’ hospital because of muscle weakness and sensory disturbance in extremities. She showed weakness, muscle atrophy and sensory abnormality in 4 limbs with patchy distribution, suggesting involvement of multiple peripheral nerve trunks. Serum titers of anti-SS-A, SS-B, and antinuclear antibody were elevated. Sural nerve biopsy showed recanalization and lymphocytic infiltration in the epineural small vessels, suggesting the presence of vasculitis. She was diagnosed as having vasculitic neuropathy complicated with Sjogren's syndrome. Methylprednisolone pulse therapy followed by oral prednisolone was started and these symptoms gradually improved in 1 month. At age 63, she felt dysesthesia in the right lower limb and this sensory abnormality spread to upper limbs. Two years later, she was admitted again due to clumsiness of hands and gait disturbance. Neurological examination showed decreased vibration and position sense of lower limbs and limb ataxia in addition to dysesthesia. Electrophysiological studies demonstrated significant decrease in amplitude of sensory nerve action potentials and delayed somatosensory evoked potentials after N13, indicating impairment of dorsal root ganglions. She was treated with IVIG (400 mg/kg, total 15 g/day) for 5 days. One week later, sensory ataxia was improved. It has been known that Sjogren's syndrome is often complicate with various types of neuropathies including vasculitic neuropathy and sensory neuropathy. This patient developed these 2 different types of neuropathies, which were dramatically improved after 2 different therapeutic regimens; indicating the importance to select a suitable treatment regimen in accordance with the mechanism of neuropathy associated with Sjogren's syndrome.
De Toni Franceschini et al (2011) reported on the case of a 64-year old woman, with asthma and sinusal polyposis in her medical history, who suddenly developed a painful polyneuropathy with diplopia. Nerve conduction studies, performed at the very onset of the neuropathy, could not definitely rule out a Guillain-Barre syndrome (GBS) and high-dose IVIG was administered. Clinical and laboratory findings subsequently supported the diagnosis of Churg-Strauss syndrome; corticosteroid therapy was started and clinical stabilization of neuropathy was apparently achieved. No indicators of unfavorable outcome were present at that time. Nevertheless, 30 days after the onset the patient acutely worsened with severe polyneuropathy relapse and fatal systemic diffusion to heart, kidney and mesenteric district, which a single cyclophosphamide pulse failed to control. The authors stated that this case highlighted the possibility that a GBS-like onset of Churg-Strauss syndrome neuropathy should be regarded as a part of multi-organ, severe or even life-threatening vasculitic involvement, requiring the most aggressive treatments, regardless of the presence of recognized factors of poor outcome.
Moreover, an UpToDate review on "Treatment and prognosis of nonsystemic vasculitic neuropathy" (Bhattacharyya and Helfgott, 2020) did not mention the use of IVIG as a therapeutic option.
Thus, there is insufficient evidence to support the use of IVIG for the treatment of vasculitic polyneuropathy.
An UpToDate review on "Treatment and prognosis of Waldenstrom macroglobulinemia" (Ansell, 2021) stated the following "Plasmapheresis alone, corticosteroids, and intravenous immune globulin (IVIG) have little or no value in this setting"..
The Austrialian National IVIg Criteria Review Working Group (NICRWG)'s guideline on "Criteria for the clinical use of intravenous immunoglobulin" (2012) concluded that the evidence for IVIG for autonomic ganglionopathy is insufficient (level 4a evidence -- small case studies only) and should be used only in exceptional circumstances -- such as in urgent or life-threatening circumstances, or in circumstances in which significant morbidity would be expected and other clinically appropriate standard therapies have been either exhausted or are contraindicated.
Simon et al (2013) evaluated the likelihood of response to IVIG by studying consecutive patients presenting with progressive, asymmetric, pure lower motor neuron (LMN) limb weakness, and determined the clinical phenotype of those who respond. A total of 31 consecutive patients with progressive, focal-onset LMN limb weakness, without evidence of clinical upper motor neuron signs; sensory, respiratory, or bulbar involvement; or evidence of motor nerve conduction block on electrodiagnostic studies, were prospectively included in this study. Each patient underwent treatment with IVIG (2 g/kg body weight) for a minimum of 3 months. Electrodiagnostic studies, a neuromuscular symptom score, and expanded Medical Research Council sum score were documented before and after IVIG treatment. The final diagnosis was determined after prolonged clinical follow-up. Only 3 of 31 patients (10 %) responded to IVIG. All responders demonstrated distal upper limb-onset weakness, EMG abnormalities confined to the clinically weak muscles, and a normal creatine kinase. This set of features was also identified in 31 % of non-responders presenting with distal upper limb weakness. Sex, age at onset, number of involved limb regions, and the duration of symptoms before treatment were not significantly different between groups. The authors concluded that the findings of this study do not support uniform use of IVIG in patients presenting with progressive asymmetric LMN limb weakness. It is suggested that IVIG treatment be limited to patients who demonstrate clinical and laboratory features suggestive of multifocal motor neuropathy. This study provided Class IV evidence that IVIG will not improve muscle function in 90 % of patients with progressive, asymmetric, pure LMN weakness.
McMahan et al (2014) highlighted novel therapies that are being used in SSc. Therapeutic interventions in SSc generally target at least 1 of 3 ongoing biological processes characteristic of the disease: vasculopathy, autoimmunity and tissue fibrosis. Treatment decisions in SSc are determined by the level of disease activity and the degree of specific organ involvement. Traditional therapy has primarily focused on organ-specific management without clear evidence of overall disease modification. The authors provided a review of a variety of agents, which are already used for other autoimmune diseases, that are now being used to treat active SSc skin or lung disease, including rituximab, tocilizumab and IVIG. Several agents studied in-vitro and in animal models of fibrosis have shown promise, including bortezomib, LPA-1 antagonists, anti-CCN2 therapy, anti-IL-13 and thrombin antagonists. The authors also provided details on targeting intracellular molecular pathways and matricellular proteins, which is another novel area of investigation. The authors concluded that combination therapy may be necessary to control the complex biological network active in SSc. They noted that most of the current evidence that suggest benefit of these agents is based on small population studies; ultimately well-designed clinical trials are needed to define the role of these agents in treating SSc.
An UpToDate review on "Overview of the treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents" (Horton and Steuber, 2019) does not mention IVIG as a management tool. Furthermore, the National Comprehensive Cancer Network’s clinical practice guideline on "Acute Lymphoblastic Leukemia" (Version 1.2014) does not mention IVIG as a management toll.
Toledano et al (2014) evaluated a trial of immunotherapy (IT) as an aid to diagnosis in suspected autoimmune epilepsy. These investigators reviewed the charts of 110 patients seen at the authors’ autoimmune neurology clinic with seizures as a chief complaint. A total of 29 patients met the following inclusion criteria:- autoimmune epilepsy suspected based on the presence of greater than or equal to 1 neural autoantibody (n = 23), personal or family history or physical stigmata of autoimmunity, and frequent or medically intractable seizures; and
- initiated a 6- to 12-week trial of IV methylprednisolone (IVMP), IVIG, or both.
Patients were defined as responders if there was a 50 % or greater reduction in seizure frequency. Eighteen patients (62 %) responded, of whom 10 (34 %) became seizure-free; 52 % improved with the first agent. Of those receiving a second agent after not responding to the first, 43 % improved. A favorable response correlated with shorter interval between symptom onset and treatment initiation (median 9.5 versus 22 months; p = 0.048). Responders included 14/16 (87.5 %) patients with antibodies to plasma membrane antigens, 2/6 (33 %) patients seropositive for glutamic acid decarboxylase 65 antibodies, and 2/6 (33 %) patients without detectable antibodies. Of 13 responders followed for more than 6 months after initiating long-term oral immunosuppression, response was sustained in 11 (85 %). The authors concluded that these retrospective findings justified consideration of a trial of IT in patients with suspected autoimmune epilepsy. This study provided Class IV evidence that in patients with suspected autoimmune epilepsy, IVMP, IVIG, or both improve seizure control. The main drawbacks of this study were its small sample size (n = 29), a retrospective design, and the lack of systematic cross-over (from IVMP to IVIG or vice versa). Furthermore, likely confounders such as anti-epileptic drug medication changes during the trial could not be controlled for and non-responders may have been lost to follow-up. The authors stated that a RCT with a cross-over design would help to further specify treatment effect and would limit confounders.
In an editorial that accompanied the afore-mentioned study, Ruegg and Panzer (2014) stated that "These results lay the foundation for a randomized controlled trial of IT in presumed autoimmune epilepsy, which would compare standardized treatment groups, thereby eliminating biases with regards to treatment choice and disease severity. This study should also pave the way for additional prospective studies regarding the natural history of autoimmune PRE [pharmaco-resistant epilepsy] and serves to raise awareness of the role of IT in the treatment of refractory epilepsies".
Rogosnitzky and colleagues (2012) stated that Crohn's disease (CD) is a debilitating condition that still requires improvement in its management. There is a need for alternatives to anti-tumor necrosis factor (TNF) drugs that are costly and beneficial in less than 50 % of patients. Intravenous immunoglobulin (IVIG) has been used in the management of aminosalicylate- and steroid-resistant CD for more than 20 years, although the published literature available is limited. A literature search identified 17 relevant publications since 1969, including 5 case reports of single patients, 2 abstracts, 3 conference papers, 1 review paper and 6 book or journal articles. No randomized controlled trials (RCTs) of IVIG in CD have been published. A review of the evidence identified indicated that IVIG can induce a rapid and significant improvement in aminosalicylate- and steroid-resistant CD, often within days of the initial administration. Data from longer-term studies showed that maintenance of remission over the medium-term is also possible. The authors concluded that these encouraging findings provided a rationale for the initiation of larger RCTs of IVIG in CD with the aim of providing further treatment options for this difficult-to-manage condition.
Furthermore, UpToDate reviews on "Management of severe or refractory ulcerative colitis in children and adolescents" (Bousvaros, Setty, and Kaplan, 2021), "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease" (Hashash and Regueiro, 2021) and "Medical therapies for Crohn disease in children and adolescents" (Zitomersky and Bousvaros, 2021) do not mention the use of IVIG/intravenous immunoglobulin as a therapeutic option.
An UpToDate review on "Overview of colon polyps" (Macrae, 2021) states that "Cronkhite-Canada syndrome is a rare, nonfamilial disorder of unknown etiology associated with alopecia, cutaneous hyperpigmentation, gastrointestinal polyposis, onychodystrophy, diarrhea, weight loss, and abdominal pain. The polyps are hamartomas and do not appear neoplastic pathologically. Characteristic features include myxoid expansion of the lamina propria and increased eosinophils in the polyps. There is some evidence that the disorder may be immune-mediated, since it may respond to immunosuppressive therapy and, in some patients, immunostaining of the polyps for IgG4 is positive. Five-year mortality rates as high as 55 percent have been reported with most deaths due to gastrointestinal bleeding, sepsis, and congestive heart failure. Treatment has included nutritional support, glucocorticoids, azathioprine, acid suppression, and antibiotics, but no specific treatment has proven to be consistently effective". This review does not mention IVIG as a therapeutic option.
Louis et al (2014) stated that IVIG is used in neonates with isoimmune hemolytic disease to prevent exchange transfusion (ET). However, studies supporting IVIG had methodological issues. These researchers updated the systematic review of safety and effectiveness of IVIG in neonates with isoimmune hemolytic disease. MEDLINE, Embase databases and Cochrane Central Register of Controlled Trials (Cochrane Library) were searched (from inception to May 2013) for randomized or quasi-randomized controlled trials comparing IVIG with placebo/controls in neonates with isoimmune hemolytic disease without any language restriction. Three investigators assessed methodological quality of included trials. Meta-analyses were performed using random effect model and risk ratio (RR)/risk difference (RD) and mean difference with 95 % CI calculated. A total of 12 studies were included; 10 trials (n = 463) of Rh isoimmunization and 5 trials (n = 350) of ABO isoimmunization (3 studies had both population). Significant variations in risk of bias precluded an overall meta-analysis of Rh isoimmunization. Studies with high risk of bias showed that IVIG reduced the rate of ET in Rh isoimmunization (RR 0.23, 95 % CI: 0.13 to 0.40), whereas studies with low risk of bias that also used prophylactic phototherapy did not show statistically significant difference (RR 0.82, 95 % CI: 0.53 to 1.26). For ABO isoimmunization, only studies with high risk of bias were available and meta-analysis revealed efficacy of IVIG in reducing ET (RR 0.31, 95 % CI: 0.18 to 0.55). The authors concluded that the effectiveness of IVIG is not conclusive in Rh hemolytic disease of newborn with studies with low risk of bias indicating no benefit and studies with high risk of bias suggesting benefit. They stated that the role of IVIG in ABO disease is not clear as studies that showed a benefit had high risk of bias.
Beken et al (2014) noted that there is still no consensus on the use of IVIG in ABO hemolytic disease of the newborn routinely. These investigators examined if administration of IVIG to newborns with ABO incompatibility is necessary. A total of 117 patients with ABO hemolytic disease and positive Coombs test were enrolled into the study. The subjects were healthy except jaundice. Infants were divided into 2 groups: Group I (n = 71) received 1 dose of IVIG (1 g/kg) and LED phototherapy; and Group II (n = 46) received only LED phototherapy. One patient received erythrocyte transfusion in Group I, no exchange transfusion was performed in both groups. Mean duration of phototherapy was 3.1 ± 1.3 days in Group I and 2.27 ± 0.7 days in Group II (p < 0.05). Mean duration of hospital stay was 5.34 ± 2.2 days in Group I and 3.53 ± 1.3 days in Group II (p < 0.05). Mean duration of phototherapy was 4.0 ± 1.5 days and 2.73 ± 1.1 days in double and single doses of IVIG, respectively, and this was statistically significant (p < 0.05). The authors concluded that IVIG therapy didn't decrease neither phototherapy nor hospitalization duration in infants with ABO hemolytic disease. They stated that meticulous follow-up of infants with ABO hemolytic disease and LED phototherapy decreased morbidity; IVIG failed to show preventing hemolysis in ABO hemolytic disease.
An UpToDate review on "Brachial plexus syndromes" (Bromberg, 2021) does not mention the use of IVIG as a therapeutic option.
UpToDate reviews on "Diagnosis and management of solitary extramedullary plasmacytoma" (Rajkumar, 2020) and "Diagnosis and management of solitary plasmacytoma of bone" (Rajkumar, 2020) do not mention IVIG as a therapeutic option.
An UpToDate review on "Postural tachycardia syndrome" (Cheshire, 2021) does not mention the use of IVIG as a therapeutic option for POTS.
Parambil and colleagues (2011) noted that small fiber neuropathy (SFN) is commonly associated with sarcoidosis and can cause significant morbidity to afflicted patients. The appropriate treatment of this condition, when associated with sarcoidosis, is not well -established. These investigators presented the findings of case series of 3 patients with sarcoidosis and SFN. The presenting clinical features, skin biopsy results, autonomic reflex screen and quantitative sudomotor axon reflex testing (QSART) findings, and response to therapy are delineated. They described 3 patients with biopsy-proven sarcoidosis who developed intractable neuropathic pain and/or symptoms related to associated autonomic dysfunction despite treatment with various immunosuppressive medications and narcotic analgesics. QSART showed evidence of a post-ganglionic sudomotor abnormality in 1 patient and was normal in the other 2. Skin biopsy findings were abnormal, demonstrating a non-length-dependent sensory SFN in all 3 patients. Painful neuropathic symptoms, as well as symptoms related to dysautonomia from SFN responded significantly to treatment with intravenous immunoglobulin (IVIG). The authors concluded that IVIG appears to be effective in relieving symptoms from SFN associated with sarcoidosis, suggesting an underlying immune mechanism. Moreover, they stated that larger prospective, controlled studies would be needed to confirm this response to IVIG and to further elucidate the underlying pathobiology behind this association with sarcoidosis
Tzekou and Fehlings (2014) stated that neuroinflammation plays an important role in the secondary pathophysiological mechanisms of spinal cord injury (SCI) and can exacerbate the primary trauma and thus worsen recovery. Although some aspects of the immune response are beneficial, it is thought that leukocyte recruitment and activation in the acute phase of injury results in the production of cytotoxic substances that are harmful to the nervous tissue. Therefore, suppression of excessive inflammation in the spinal cord could serve as a therapeutic strategy to attenuate tissue damage. The immunosuppressant methylprednisolone has been used in the setting of SCI, but there are complications which have attenuated the initial enthusiasm. Hence, there is interest in other immunomodulatory approaches, such as IVIG. Importantly, IVIG is used clinically for the treatment of several auto-immune neuropathies, such as GBS, CIDP and Kawasaki disease, with a good safety profile. Thus, it is a promising treatment candidate for SCI. Indeed, IVIG has been shown by these researchers to attenuate the immune response and result in improved neurobehavioral recovery following cervical SCI in rats through a mechanism that involves the attenuation of neutrophil recruitment and reduction in the levels of cytokines and cytotoxic enzymes. The authors reviewed published data in the context of relevant mechanisms of action that have been proposed for IVIG in other conditions. They hoped that this discussion will trigger future research to provide supporting evidence for the efficiency and detailed mechanisms of action of this promising drug in the treatment of SCI, and to facilitate its clinical translation.
Xie and colleagues (2015) noted that Clarkson disease (systemic capillary leak syndrome) is a highly rare disorder of unknown etiology. The disease is characterized by episodes of transient vascular collapse, which leads to hypotensive shock and anasarca. Previous treatment of this potentially devastating condition has been largely ineffective. In a longitudinal follow-up study, these researchers evaluated IVIG prophylactic therapy in a cohort of 29 patients with Clarkson disease. All patients received treatments at the discretion of their primary providers and retrospectively via questionnaire recorded symptoms beginning with their first documented episode of the disease until May 31, 2014. Twenty-two out of 29 patients (76 %) responded to the questionnaire, and 18 out of the 22 respondents received monthly prophylaxis with IVIG during the study period for a median interval of 32 months. The median annual attack frequency was 2.6/patient prior to IVIG therapy and 0/patient following initiation of IVIG prophylaxis (p = 0.001); 15 out of 18 subjects with a history of 1 or more acute Clarkson disease episodes experienced no further symptoms while on IVIG therapy. The authors concluded that IVIG prophylaxis is associated with a dramatic reduction in the occurrence of systemic capillary leak syndrome attacks in most patients, with minimal side effects. They stated that a prospective, randomized trial is needed to fully evaluate the benefits of IVIG for Clarkson disease and to determine optimal dosage and duration of therapy.
Preparation for Thymoma Surgery (To Prevent Myasthenia Exacerbation)
An UpToDate review on "Overview of the treatment of myastenia gravis" (Bird, 2021) states that "Need for thymectomy -- In parallel with symptomatic treatment and immunotherapeutic agents for MG, we consider thymectomy because of its potential longer-term benefit …. For patients with preoperative bulbar or respiratory symptoms, we try to defer surgery until they are reasonably well controlled. We administer IVIG or perform a series of plasma exchanges one or two weeks before surgery, if these respiratory or bulbar symptoms persist. The exact timing of surgery and what techniques are appropriate are issues not settled".
Alpha-1 Antitrypsin Deficiency
An UpToDate review on "Treatment of alpha-1 antitrypsin deficiency" (Stoller, 2021) does not mention IVIG as a therapeutic option.
Cellular (T-Cell) Mediated Renal Transplant Rejection
Acute allograft (organ) rejection may be cellular (T-cell mediated) or humoral (antibody-mediated) (AHR, AMR). Available evidence indicates that pre-treatment with intravenous immunoglobulins (IVIG) (desensitization) may reduce the risk of AMR in highly sensitized renal transplant patients. However, there is a scarcity of data regarding the effectiveness of IVIG for the T-cell mediated rejection.
An UpToDate review on "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the renal allograft"(Brennan and Malone, 2020) does not mention IVIG.
Evans Syndrome
Mathew et al (1997) conducted a retrospective survey to assess the demography, presentation, clinical course, and treatment response of children with Evans syndrome. Information was analyzed from a detailed questionnaire completed by pediatric hematologists mainly in the U.S. and Canada. These investigators sought information regarding demographics, findings at presentation, approach to diagnosis, treatments used (with specific reference to splenectomy, corticosteroids, and intravenous immunoglobulin (IVIG)), course of the disease with emphasis on recurrences, and status at last follow-up. A total of 42 patients (22 males, 20 females) were included in the study. The median age was 7.7 years (range of 0.2 to 26.6 years). At presentation, thrombocytopenia (32 patients) and anemia (28) were common; neutropenia occurred in 10 and pancytopenia in 6. Patients received a median of 5 (range of 0 to 12) modalities of treatment. Courses of IVIG and corticosteroids were given to almost all patients; responses were varied but the effects lasted as long as 2 years. Splenectomy was performed for 15 patients but the median duration of response was only 1 month. Other treatments included cyclosporine, vincristine, danazol, azathioprine, cyclophosphamide, and plasmapheresis. The course of the disease was characterized by recurrent thrombocytopenia, hemolytic anemia, and neutropenia. After a median follow-up of 3 years, 3 patients had died, 20 had active disease on treatment, 5 had persistent disease (not on treatment), and 14 had no evidence of disease. The authors concluded that Evans syndrome is a chronic and recurrent condition that is often refractory to IVIG, corticosteroids, and splenectomy. Responses to other agents have been anecdotal and inconclusive. They stated that a prospective study involving these agents is needed to determine optimal therapeutic combinations.
The "Guidelines on the use of intravenous immune globulin for hematologic conditions" (Anderson et al, 2007) noted that Evans syndrome was also reviewed by the expert panel, but specific recommendations were not made for this condition. The guidelines also noted that Evans syndrome has a very poor response rate to any therapy, including IVIG, where initial responses are poor and transient, relapse is high, and subsequent responses worse. Evidence regarding IVIG use in Evans syndrome has focused on the pediatric population, and generalization to the adult population, given the complexity of the syndrome, is probably not appropriate. The role of IVIG is difficult to ascertain because most treatment options focus on multi-agent regimens.
The United Kingdom’s Department of Health’s "Clinical guidelines for the use of intravenous immunoglobulins" (Provan et al, 2007) selected IVIG for the acute treatment of Evan syndrome, but not as maintenance therapy for the condition. (Grade of Evidence: C [Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV)], III [Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies]).
The criteria for the clinical use of IVIG in Australia (2011) indicated the evidence of the use of IVIG for Evans syndrome consisted of small case studies only; insufficient data (Category 4a).
In a Medscape review on "Evans syndrome treatment & management", Mathew (2014) stated that "Patients with persistent immune cytopenia and those who require prolonged or high doses of steroids may benefit from IVIG (e.g., 1 to 2 g/kg/day for 1 to 2 days. Their thrombocytopenia is more likely to respond than their hemolysis is. Long-term control of thrombocytopenia is reportedly achieved with interval doses of IVIG".
Jaime-Perez et al (2015) documented the experience of one referral service with patients diagnosed with Evans syndrome, the treatment and response and reviewed current treatment strategies and results. Patients enrolled in this study fulfilled criteria for Evans syndrome. Data were retrieved from the clinical files and electronic databases of the Department of Hematology, Hospital Universitario "Dr. José Eleuterio González". Treatment modalities and response and the use of additional therapies were evaluated. The literature was reviewed in the context of the clinical course of the studied patients. A total of 6 patients were diagnosed with Evans syndrome in the study period. Patient 1 was treated with steroids, relapsed twice and was again treated with steroids. Patient 2 treated initially with steroids plus IVIG was subsequently lost to follow-up. A good response was achieved in Patients 3 and 4, who were treated with steroids plus rituximab; patient 4 also received danazol as a second-line therapy. However both relapsed and subsequently underwent splenectomy at 10 and 9 months, respectively. One patient, number 5, treated with steroids, danazol and rituximab did not relapse within 4 years of follow-up and Patient 6, who received steroids plus danazol did not relapse within 3 years of follow-up. The authors concluded that Evans syndrome is an uncommon hematologic condition rarely diagnosed and not widely studied. Clinicians must have it in mind when evaluating a patient with a positive direct anti-globulin test, anemia and thrombocytopenia, since prognosis depends on its early recognition and opportune therapy, but even this leads to variable results. (Only 1 of the 6 patients was treated with IVIG plus steroid; and was lost to follow-up).
Hereditary Motor and Sensory Neuropathy (including Charcot Marie Tooth)
UpToDate reviews on "Hereditary sensory and autonomic neuropathies" (Eichler, 2021) did not mention IVIG as a therapeutic option.
Interstitial Lung Disease
Suzuki et al (2009) stated that interstitial lung disease (ILD) associated with polymyositis/dermatomyositis (ILD-PM/DM), including amyopathic dermatomyositis (ADM), is recognized as an important condition because it frequently causes death, despite intensive therapy with high-dose corticosteroid and immunosuppressive agents, such as cyclosporine A and cyclophosphamide. Intravenous immunoglobulin therapy (IVIG) has shown efficacy for myopathy associated with PM/DM, but its usefulness for ILD-PM/DM is unclear. This study was designed to investigate the effectiveness of IVIG for refractory ILD-PM/DM. A review was made of medical charts of 5 patients (2 men and 3 women) who were treated with IVIG for refractory ILD-PM/DM resistant to high-dose corticosteroid and cyclosporine A and/or cyclophosphamide. One patient had acute ILD-PM and 4 patients had acute ILD-ADM. Of the 5 patients, 1 patient with ILD-PM and 1 patient with ILD-ADM survived. No adverse reactions were seen due to IVIG treatment. There were no critical differences in the clinical parameters and clinical courses between survivors and non-survivors. The authors concluded that IVIG treatment is safe and could be an effective salvage therapy for refractory ILD-PM/DM in certain cases, suggesting that further controlled trials are worthwhile.
Also, UpToDate reviews on "Treatment and prognosis of nonspecific interstitial pneumonia" (Flaherty, 2021) and "Interstitial lung disease in rheumatoid arthritis" (Lake, 2021) do not mention IVIG as a therapeutic option.
An UpToDate review on "Interstitial lung disease in dermatomyositis and polymyositis: Treatment" (Dellaripa and Danoff, 2020) states that "A number of case reports and case series have suggested that intravenous immune globulin (IVIG) is effective for ILD associated with DM or PM. Further data from trials of IVIG will be valuable to assess its role in treating myositis ILD".
An UpToDate review on "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)" (Varga, 2021) states that "Investigational approaches -- Several other potential therapies for SSc-ILD are under investigation, including mycophenolate mofetil, hematopoietic cell transplantation. Additionally, agents that have efficacy in the treatment of idiiopathic pulmonary fibrosis (IPF), such as pirfenidone, are undergoing evaluation in SSc-ILD".
Juvenile Systemic Sclerosis
The Childhood Arthritis and Rheumatology Research Alliance (CARRA) Localized Scleroderma Workgroup’s consensus statement on "Treatment plans for juvenile localized scleroderma" (Li et al, 2012) had no recommendation for the use of IVIG.
An eMedicine’s review on "Juvenile Systemic Sclerosis Treatment & Management" (Person, 2014) had no recommendations for IVIG.
An UpToDate review on "Juvenile localized scleroderma" (Zulian,2021) does not mention IVIG as a therapeutic option.
Furthermore , the American College of Rheumatology’s Web Information on "Localized Scleroderma (Juvenile)" (2015) does not list IVIG as a therapeutic option.
Oral Lesions/Ulcers
An UpToDate review on "Oral lesions" (Lodi, 2020) does not mention IVIG as a therapeutic option.
Orbital Myositis
In a review on "Orbital myositis, idiopathic inflammatory myopathies -- Recent developments" (Kubota, 2011) as well as a review on "Idiopathic inflammation of the orbit and contiguous structures" (Shinder et al, 2012), IVIG was not mentioned as a therapeutic option.
Rh(D) Alloimmunization in Pregnancy
In a pilot study, Deka et al (2013) examined the usefulness of direct fetal IVIG infusion along with IUT in the management of severe fetal anemia in rhesus (Rh) alloimmunized pregnancies. A total of 34 consecutive Rh-isoimmunized pregnant women who required serial IUTs received either blood alone (control group, n = 16) or IVIG and blood (study group, n = 18). Pregnancies were followed up to delivery, and fetal outcome was recorded. The rate of fall of hematocrit was measured and compared between the 2 groups. There was a slower rate of fall of hematocrit in the study group (IUT and IVIG) compared to the control group (only IUT). The mean rate of fall was 0.72 ± 0.54 % per day in the study group while it was 1.29 ± 0.95 % per day in the control group (p = 0.005). The authors concluded that the fall of fetal hematocrit was reduced in the study group. The results of this pilot study can be used to time the next transfusion in patients receiving IVIG along with IUT (taking the rate of fall as 0.70 %). This may eventually result in decreasing the number of transfusions per fetus.
Furthermore, an UpToDate review on "RhD alloimmunization in pregnancy: Overview" (Moise, 2021) states that "Management of pregnancies complicated by alloimmunization -- Management of pregnancies complicated by maternal alloimmunization involves determining the fetal Rh(D) type and monitoring for fetal anemia if the fetus is Rh(D) positive. Monitoring may involve following maternal anti-D titers or ultrasound assessment of fetal middle cerebral artery peak systolic velocity. Severe fetal anemia near term is treated by delivery for neonatal treatment; remote from term, intrauterine fetal transfusions are performed. Serial combined maternal plasmapheresis and intravenous immune globulin therapy is a promising approach for decreasing the severity of fetal disease when there is a significantly elevated titer (eg, >1:256) or a history of previous severe hemolytic disease of the fetus and newborn (HDFN; eg, fetal or neonatal death due to HDFN or need for intrauterine transfusion [IUT] before 24 weeks of gestation) ".
Scleritis
An UpToDate review on "Treatment of scleritis" (Dana and Papaliodis, 2021) does not mention IVIG as a therapeutic option.
Livedoid Vasculitis
Bounfour et al (2013) stated that livedoid vasculopathy (LV) is a thrombotic vasculopathy of the skin of unknown origin. No treatment has been validated in this indication, but case reports suggested the successful use of intravenous immunoglobulins (IVIG) in LV. Outcomes in 5 patients treated with IVIG for treatment-resistant ulcerated LV were retrospectively analyzed. Treatment with IVIG induced complete remission (based on clinical evaluation and a pain-related visual analog scale) in 4 patients but was ineffective in 1 patient; 3 patients relapsed; the median time to relapse was 10.7 months. Re-treatment with IVIG in these 3 patients was successful. The authors concluded that these cases confirmed previous reports that IVIG appeared to be a rapid, effective, and safe treatment for patients with idiopathic refractory ulcerated LV. However, they stated that a placebo-controlled study is mandatory to confirm these results.
Monshi et al (2014) noted that evidence for the efficacy of various therapies of LV is limited. These researchers determined the tolerability and effectiveness of 2 g/kg of IVIG every 4 weeks in patients with LV. This was a long-term follow-up study of 11 patients with LV treated with 2 g/kg of IVIG assessing the clinical characteristics, disease course, and quality of life. The treatment regimen led to complete remission of ulcerations and pain in 17 of 29 disease episodes (59 %) after 3 cycles and in 25 of 29 episodes (86 %) after 6 cycles. Two disease episodes showed remission after 7 and 8 cycles, resulting in a total number of remissions of 27 (93 %). Sub-score analysis showed resolution of pain in 80 % after 2 IVIG cycles. Disease severity and quality of life were significantly improved after 6 cycles. Median duration of remissions was 26.7 months after initial and 7.5 months after subsequent disease episodes. The authors concluded that in these patients with LV, high-dose IVIG led to fast and complete resolution of pain and ulcerations and to substantial improvement in quality of life. The main drawback of this study was that this was a small (n = 11) retrospective study that did not include the comparison of IVIG efficacy and its impact on quality of life with treatment options.
Kim et al (2015) stated that LV is a thrombotic vasculopathy of the skin of unknown origin. No treatment has been validated in this indication, but case reports demonstrated successful use of IVIG in LV. These investigators assessed the tolerability and effectiveness of 2 g/kg IVIG therapy every month for 2 to 3 cycles in patients with refractory LV. They analyzed the efficacy, side effects and recurrence after long-term follow-up (51.9 ± 14.0 months) in 7 patients with LV treated with 2 g/kg of IVIG. Mean clinical score of sum of erythema, ulceration and pain index (each: 0 to 3) was 5.7 ± 0.9 before the therapy and significantly lower after therapy (1.1 ± 0.5) (p = 0.001). Even after just 1 cycle of IVIG, the score decreased significantly from 5.7 ± 0.9 to 3.7 ± 0.9 (p = 0.002), especially the pain score. In 1 patient, LV has not recurred for over 7 years; 6 patients experienced recurrence after a mean of 12.7 ± 2.8 months. Out of the 6 patients, 2 were re-administered IVIG whereas the others were well-controlled by conventional therapy. The authors proposed that IVIG is a rapid, effective, and safe therapeutic option in LV refractory to other treatment modalities. This was a small (n = 7) study.
An eMedicine review on "Livedoid Vasculopathy Treatment & Management" (Scheinfeld, 2015) states that "Some reports have noted that intravenous immunoglobulin can be useful in treating atrophie blanche and livedoid vasculopathy, but this remains an experimental treatment".
An UpToDate review on "Livedoid vasculopathy" (Davis, 2020) considers intravenous immune globulin (monthly infusions of 0.5 g/kg given over two or three consecutive days as may be useful in livedoid vasculopathy based upon case reports or small case series.
Necrotizing Myopathy
Petiot et al (2013) stated that necrotizing autoimmune myopathies (NAMs) are included in the spectrum of inflammatory myopathies, together with polymyosis (PM), dermatopolymyosis (DPM) and inclusion body myositis (IBM), despite the characteristic feature of marked muscular necrosis without inflammatory infiltrates. The clinical presentation is highly variable, often similar to the other inflammatory myopathies. The most common finding is nevertheless the severe form with rhabdomyolysis. The creatine kinase level is elevated (around 10,000 IU/L) and electromyography shows myopathic changes with increased spontaneous activities reflecting the importance of the muscular necrosis. Muscle biopsy is required for diagnosis, revealing active necrosis of the muscle fibers without inflammatory invasion by CDA+ or CD8+ T-cells. Deposition of a microvascular membrane attack complex (C5b9) is often noted, whereas the up-regulation of MHC class 1 is rarely detected. Signs of endomysial microangiopathy are frequently reported. Necrotizing autoimmune myopathies can be associated with anti-signal recognition particle (SRP) antibodies or more rarely with the usual inflammatory myopathy antibodies. Paraneoplasic forms were described but remain exceptional. Lastly, NAMs, sometimes associated with statin therapy, have been recently described. They are linked with an antibody directed against 3-hydroxy-3-methyglutaryl-coenzyme A. The authors noted that treatment is based on corticosteroid therapy, immunosuppressive drugs or IVIGs; response is variable, depending on the clinical form.
Patil and associates (2015) stated that necrotizing myopathy with pipe-stem capillaries is a form of chronic inflammatory myopathy, with histopathology showing necrotizing myopathy, minimal cellular infiltration, and microangiopathy. These researchers presented the case of a 30-year old female with progressive limb weakness of 6 months, with skin pigmentation and Raynaud's phenomenon. Serum creatine phosphokinase was 3,990 U/L. Muscle biopsy showed necrotic fibers, focal sparse perivascular inflammation/perifascicular atrophy, endomysial/epimysial vessel wall thickening with luminal narrowing. The features were of inflammatory necrotizing myopathy and neuropathy with pipe-stem capillaries/microangiopathy. She was pulsed with IVIG, methylprednisolone, and cyclophosphamide and showed a good improvement. The authors concluded that in the absence of widespread inflammatory response and classical histopathology findings, it is important to diagnose this condition as it showed a good response to aggressive and prolonged immunotherapy. This was a single-case study; and its findings were confounded by the combinational use of IVIG, methylprednisolone, and cyclophosphamide.
Ramanathan and co-workers (2015) examined a cohort of Australian patients with statin exposure who developed NAM associated with a novel autoantibody against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and described the clinical and therapeutic challenges of managing these patients and an optimal therapeutic strategy. Clinical, laboratory, EMG, and histopathologic results and response to immunomodulation were reported in 6 patients with previous statin exposure and antibodies targeting HMGCR. All patients presented with painless proximal weakness following statin therapy, which persisted after statin cessation. Serum creatine kinase levels ranged from 2,700 to 16,200 IU/L; EMG was consistent with a myopathic picture. Muscle biopsies revealed a pauci-immune necrotizing myopathy. Detailed graphical representation of the clinical course of these patients showed a close association with rising CK and an increase in clinical weakness signifying relapses, particularly upon weaning or ceasing steroids. All 6 patients were responsive to initial steroid therapy, with 5 relapsing upon attempts to wean steroids. Both CK and clinical strength improved with the re-institution of immunotherapy, in particular steroids and IVIG. All patients required treatment with varying multi-agent immunosuppressive regimens to achieve clinical remission, including prednisone (n = 6), IVIG (n = 5), plasmapheresis (n = 2), and additional therapy including methotrexate (n = 6), cyclophosphamide (n = 2), rituximab (n = 2), azathioprine (n = 1), and cyclosporine (n = 1). The authors concluded that recognition of HMGCR antibody-associated NAM is important because these patients are responsive to immunosuppression, and early multi-agent therapy and a slow and cautious approach to withdrawing steroids may improve outcomes.
Furthermore, an UpToDate review on "Statin muscle-related adverse events" (Rosenson and Baker, 2021) does mention treatment with oral steroid, intravenous immunoglobulin (IVIG) and/or rituximab be reasonable and safe for as a therapeutic option for immune-mediated necrotrizing myopathy.
Ocular Myasthenia Gravis
Mittal and colleagues (2011) noted that the frequency of ocular myasthenia gravis (OMG) in patients referred to an academic neuro-ophthalmology clinic for suspected MG is unknown. These researchers determined the frequency of ocular OMG in patients referred to an academic neuro-ophthalmologist and determined alternate diagnoses and response to therapy. They performed a retrospective chart review of patients presenting to the University of Kansas Neuro-Ophthalmology Clinic with suspected OMG over 9 years. These investigators defined OMG as isolated ptosis/diplopia at initial presentation supported by at least 1 of the following abnormal tests: edrophonium test, ice test, Cogan lid twitch, fatigability on sustained up-gaze, acetylcholine receptor binding antibody, greater than 10 % decrement on repetitive stimulation, or abnormal single-fiber jitter. They also determined the cause of ptosis/diplopia if it was not the result of OMG. Patients who progressed from OMG to generalized disease were termed transformed MG (TMG). A total of 138 patients were referred with mean age at presentation 58 ± 19 years. Myasthenia gravis was diagnosed in 101 patients; 95 had OMG; 6 had generalized MG (GMG). Diagnosis in the other 37 was cranial nerve palsies (9), levator dehiscence (5), multiple sclerosis (2), blepharospasm (2), decompensated phorias (3), accommodation spasm (4), exophoria (3), skew deviation (2), Graves’ disease (1), hypertropia (1), myopathy (1), neurosarcoidosis (1), progressive supranuclear palsy (1), Miller Fisher variant of Guillain-Barre syndrome (1), and obstructive sleep apnea (1). Mean follow-up was 3.0 ± 2.8 years. Test sensitivity/specificity in OMG was fatigability on sustained up-gaze 0.80/0.63; ice pack 0.80/0.25; Cogan lid twitch 0.59/1.00; edrophonium 0.88/0.50; acetylcholine receptor binding antibody 0.38/1.00; repetitive nerve stimulation 0.24/1.00; and single-fiber electromyography 0.90/1.00. Pyridostigmine was used without prednisone in 59 of 97 patients with OMG and 12 of 59 developed TMG. Prednisone was used in 38 patients; 21 of 38 (55 %) met Myasthenia Gravis Foundation of America improvement status and none had TMG. The authors concluded that the diagnosis of MG was confirmed in the majority of patients referred to the authors’ neuro-ophthalmology clinic, but 27 % did not have MG. They stated that it is possible that prednisone treatment of OMG may prevent progression to TMG, but further study is needed. This review did not mention IVIG as a therapeutic option.
Haines and Thurtell (2012) stated that myasthenia gravis (MG) is an autoimmune disorder that is characterized by variable weakness and fatigability. Often, MG presents with only ocular symptoms such as ptosis and diplopia. Treatment of ocular MG is aimed at relieving the symptoms of ptosis and diplopia, as well as preventing the development of generalized MG symptoms. Immune suppression with steroids is often the main therapy. Steroid doses must be increased slowly because of a risk of precipitating myasthenic crisis. After achieving the highest target dose, steroids are then slowly tapered down to the lowest effective dose. Often, acetylcholinesterase inhibitors such as pyridostigmine and neostigmine are also employed to help control symptoms. When steroids are contraindicated, acetylcholinesterase inhibitors can be tried as the primary therapy. Steroid-sparing agents such as azathioprine and mycophenolate may also have a role in treating OMG. Other treatments for MG include plasmapheresis, IVIG, and other immunosuppressive agents, but these are rarely required for OMG. Patients should also be evaluated for thymoma. Thymoma should be resected surgically. Ocular MG without thymoma is not usually treated with thymectomy. Topical agents may be useful as additional therapy for mild or moderate ptosis. Non-pharmacologic treatments include occlusive devices, prisms, eyelid supports, contact lenses, and (in long-standing, stable cases) strabismus surgery or eyelid elevation surgery.
The Myasthenia Gravis Foundation of America does not mention IVIG as a therapeutic option.
Furthermore, an UpToDate review on "Ocular myasthenia gravis" (Pelak and Quan, 2021) states that "Plasmapheresis and intravenous immune globulin are used for the short-term management of severe GMG (generalized MG) and are used only OMG (ocular MG) when bilateral ptosis is debilitating".
Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)
An UpToDate review on "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis" (Merola, 2020) does not mention IVIG as a therapeutic option.
Urticarial Vasculitis
An UpToDate review on "Urticarial vasculitis" (Brewer and Davis, 2020) states that "Other therapies reported in the literature include cyclophosphamide, intravenous immunoglobulin, reserpine, anti-B-cell therapy, and monoclonal antibody therapy; however, these are limited to single case reports and further evaluation is needed before they can be recommended".
Viral Myocarditis
In a Cochrane review, Robinson et al (2015) compared transplant-free survival of adults and children with presumed viral myocarditis treated with IVIG versus those who did not receive IVIG. A secondary objective was to determine if a group of patients with presumed viral myocarditis could be identified (on the basis of age, duration of symptoms, acuity of onset of symptoms, cardiac function at presentation, virological results or the presence or absence of histological evidence of acute myocarditis on cardiac biopsy in patients in whom a biopsy was performed) who would be the most likely to benefit from IVIG. These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 12 of 12), the Database of Abstracts of Reviews of Effects (DARE) (2013, Issue 4 of 4), Medline (Ovid, 1946 to Week 3 of January 2014), Embase (Ovid, 1980 to Week 4 of 2014), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO, Web of Science (Thomson Reuters, 1970 to January 24, 2014), the Latin American and Caribbean Health Science Information Database (LILACS) (1982 to January 30, 2014), trials registries and conference proceedings. These researchers contacted authors of trials and checked reference lists of relevant papers. They applied no language restrictions, and included studies if:- participants had a clinical diagnosis of acute myocarditis with a left ventricular ejection fraction (LVEF) of less than or equal to 0.45, left ventricular end-diastolic diameter (LVEDD) greater than 2 standard deviations (SDs) above the norm or a shortening fraction (SF) greater than 2 SDs below the mean with duration of cardiac symptoms of less than 6 months;
- participants had no evidence of non-infectious or bacterial cardiac disease; and
- participants were randomly assigned to receive at least 1 g/kg of IVIG versus no IVIG or placebo.
The authors excluded studies if;
- participants had received immunosuppression before outcome assessment; or
- onset of myocarditis was reported to occur less than 6 months post-partum.
Two review authors screened searches and extracted data independently. They assessed quality using the "Risk of bias" tool. Meta-analysis was not possible because only 2 relevant studies were found, and researchers analyzed markedly different populations. In this update, review authors added 1 study to the study from the original review. The first relevant study involved 62 adults with recent-onset dilated cardiomyopathy randomly assigned to receive IVIG or an equivalent volume of 0.1 % albumin in a blinded fashion. The overall risk of bias was unclear. The incidence of death or the requirement for cardiac transplant or placement of a left ventricular assist device was low in both groups (OR for event-free survival [EFS] 0.52, 95 % CI: 0.12 to 2.30). Follow-up at 6 months and at 12 months showed equivalent improvement in LVEF (MD 0.00, 95 % CI: -0.07 to 0.07 at 6 months; MD 0.01, 95 % CI: -0.06 to 0.08 at 12 months). Functional capacity as assessed by peak oxygen consumption was equivalent in the 2 groups at 12 months (MD -0.80, 95 % CI: -4.57 to 2.97). Infusion-related side effects were more common in the treated group, but all were reported to be mild (OR 30.16, 95 % CI: 1.69 to 539.42). The second study added at this update included 83 children in India with suspected viral encephalitis and myocarditis. The overall risk of bias was high. The OR for EFS was 7.39 (95 % CI: 0.91 to 59.86). Follow-up occurred only until hospital discharge, and LVEF was 49.5 % in the treated group versus 35.9 % in the placebo group (risk difference 13.6 %, 95 % CI: 5.1 to 22.1 %; p value = 0.001). The authors concluded that evidence from 1 trial did not support the use of IVIG for the treatment of adults with presumed viral myocarditis. The only pediatric trial had high risk of bias but suggested that benefit may be seen in the select group of children beyond the neonatal period who have viral encephalitis with myocarditis. They stated that until higher-quality studies have demonstrated benefit in a particular group of patients, IVIG for presumed viral myocarditis should not be provided as routine practice in any situation; and further studies of the pathophysiology of myocarditis would lead to improved diagnostic criteria, which would facilitate future research.
Asymptomatic Kidney Transplant Recipients with Donor Specific Antibodies
Matignon and associates (2017) stated that approximately 25 % of kidney transplant recipients develop de-novo anti-HLA donor-specific antibodies (dnDSA) resulting in acute antibody-mediated rejection (ABMR) in 30 % of patients. Pre-emptive therapeutic strategies are not available. These researchers conducted a prospective observational study including 11 kidney transplant recipients. Inclusion criteria were dnDSA occurring within the 1st year after transplant and normal allograft biopsy. All patients were treated with high-dose IVIG (2 g/kg at 0, 1 and 2 months post-dnDSA). The primary efficacy outcome was incidence of clinical and sub-clinical acute ABMR within 12 months after dnDSA detection as compared to a historical control group (IVIG-). Acute ABMR occurred in 2 or 11 patients in the IVIG+ group and in 1 of 9 patients in the IVIG- group. IVIG treatment did not affect either class I or class II DSA, as observed at the end of the follow-up. IVIG treatment significantly decreased FcγRIIA mRNA expression in circulating leukocytes, but did not affect the expression of any other markers of B cell activation. The authors concluded that in this first pilot study including kidney allograft recipients with early dnDSA, pre-emptive treatment with high-dose IVIG alone did not prevent acute ABMR and had minimal effects on DSA outcome and B cell phenotype.
BK Virus Induced Nephropathy
Sawinski and Goral (2015) noted that reduction of immunosuppression is the mainstay of BK virus induced nephropathy treatment. Management approaches differ and can include discontinuation of the anti-metabolite (such as MMF), dose reduction of the calcineurin inhibitor (CNI) (tacrolimus or cyclosporine) or switching from tacrolimus to cyclosporine. Other treatment alternatives can include use of leflunomide, cidofovir, ciprofloxacin, rapamycin or intravenous immunoglobulin. The review noted that objective data regarding BK treatment are limited. The review cited a meta-analysis of all published approaches to BK treatment (citing Johnston, et al., 2010) that found only 3 randomized controlled trials, 9 cohort studies and 29 case series.
An UpToDate review on "Kidney transplantation in adults: BK polyomavirus-associated nephropathy" (Limaye and Brennan, 2021) states that "We do not routinely administer IVIG for the treatment of BKPyVAN. However, the adjunctive use of IVIG may be considered in patients with established BKPyVAN who do not respond to a reduction in immunosuppression and who also have severe hypogammaglobulinemia (ie, immunoglobulin G [IgG] <400 mg/dL)".
Sener, et al. (2008) studied the outcome of renal transplant patients with BK virus associated nephropathy treated with IVIG. After 11.4 +/- 3.9 months (mean +/- SEM) from the time of transplantation, 8 renal allograft recipients were diagnosed with BK virus associated nephropathy. In addition to a reduction of immunosuppressive therapy, patients received 2 g/kg IVIG. After a mean follow-up of 15 months, all except one patient were off dialysis. The authors concluded that, after IVIG therapy, 88% of patients still have functioning grafts, although renal function continues to be impaired. "The benefit of concomitant IVIG and reduction of immunosuppressive therapy in BKVAN needs to be further addressed in randomized, multicentered trials."
Cutaneous Calcinosis
Dima and co-workers (2014) discussed the current pharmacological options of treatment in calcinosis cutis related to rheumatic diseases. These researchers performed an extensive Medline search of articles from 1970 to January 2014 using the index word "calcinosis" and the co-indexing terms "treatment", "calcium channel blocker", "diltiazem", "nifedipine", "verapamil", "amlodipine", "anticoagulant", "warfarin", "bisphosphonate", "etidronate", "pamidronate", "alendronate", "risedronate", "aluminum hydroxide", "probenecid", "antibiotic", "tetracycline", "minocycline", "ceftriaxone", "colchicine", "intravenous immunoglobulin", "sodium thiosulfate", "TNF-alpha inhibitors", "infliximab", "rituximab", "thalidomide", "corticosteroids", "stem cell transplantation". Diltiazem is recommended by some authors as 1st-line approach in calcinosis cutis and is also the therapeutic principal referred by the largest number of available publications. It appeared to be efficient in more than 50 % of the reported cases. There remained, however, a significant number of patients in which another solution must be found. The general trends observed over time are of switching the search of solutions in dystrophic calcinosis cutis related to connective tissue diseases, from therapies on calcium metabolism to therapies for the underlying disease. The new options available in the management of calcinosis cutis, like biological therapies or IVIG, appeared to be promising, but not universally successful. In children with severe forms, hematopoietic stem cell transplantation can also be taken into consideration. The authors concluded that data for all therapies proposed in calcinosis cutis is generally reported in single cases and small case series and so, the existent data is all yielding a low level of evidence.
Tayfur and colleagues (2015) retrospectively analyzed whether bisphosphonates initiated in combination with immunosuppressive drugs and/or IVIG resulted in a radiological and clinical improvement of dystrophic calcinosis in 6 female juvenile dermatomyositis (JDM) patients. Medical records of the patients were reviewed. All 6 patients met the Bohan and Peter diagnostic criteria for JDM. A resolution of calcinosis was observed in 4 of the 6 patients with JDM following the use of bisphosphonates and intensive immunosuppressive therapy with or without IVIG. Bisphosphonates were unable to either decelerate the progression of calcinosis or improve calcinosis in cases 5 and 6. In case 5, it took a relatively long time to control the disease activity despite the appropriate immunosuppressive treatment and she experienced multiple flares of active JDM. Case 6 had a long duration of severe active disease before treatment initiation. No important adverse event (AE) was observed. The authors concluded that early commencement of aggressive immunosuppressive agents in combination with bisphosphonate was a choice for the treatment of calcinosis in JDM patients; concomitant use of IVIG may have an additional effect on the resolution of calcinosis.
Furthermore, an UpToDate review on "Calcinosis cutis: Management" (Fernandez and Ward, 2021) states that "Multiple other treatments have been used for dystrophic calcinosis cutis. Like diltiazem, colchicine, and minocycline, these treatments have limited or conflicting efficacy data. Examples include warfarin, bisphosphonates, intravenous immune globulin, topical or intradermal sodium thiosulfate, oral aluminum hydroxide, intralesional corticosteroids, ceftriaxone, probenecid, and infliximab".
Diabetic Polyneuropathy
Courtney et al (2001) noted that diabetic neuropathies are universally recognized and cause significant morbidity. At present improving glycemic control is the only recognized treatment. These investigators reported on the case of a man with type 2 diabetes presented with disabling asymmetric lower limb proximal neuropathy. Rapid clinical, functional, and electrical improvement followed treatment with IVIG. The etiology of diabetic amyotrophy remains controversial; but there is evidence for an immune-mediated process and this case suggested a role for immunoglobulin in the management of this debilitating condition.
Leger and Behin (2005) conducted a critical review of recent studies on the clinical and therapeutic aspects of multi-focal motor neuropathy, and analyzed their implications for patient management. Recent studies have contributed to defining the specific position of multi-focal motor neuropathy within the spectrum of chronic immune-mediated polyneuropathies. One study compared features of this condition with multi-focal acquired demyelinating sensory and motor neuropathy, while others have focused on pathological alterations at the site of conduction blocks. A further study described 6 new cases of multi-focal acquired motor neuropathy, which should be considered as a variant of multi-focal motor neuropathy. Several Cochrane reviews and review articles have shown evidence of the effectiveness of IVIGs in the treatment of multi-focal motor neuropathy. The issue of long-term IVIGs in multi-focal motor neuropathy, however, has yielded controversial results – 2 studies have shown progressive motor deterioration in most patients, correlated with electrophysiological signs indicative of axonal degeneration, while a 3rd study found signs of sustained clinical and electrophysiological improvement after a mean follow-up of 7.25 years.
The American Academy of Neurology’s evidence-based guideline on "Intravenous immunoglobulin in the treatment of neuromuscular disorders" (Patwa et al, 2012) stated that "Evidence is insufficient to support or refute use of IVIG in the treatment of immunoglobulin M paraprotein-associated neuropathy, inclusion body myositis, polymyositis, diabetic radiculoplexoneuropathy".
Furthermore, an UpToDate review on "Management of diabetic neuropathy" (Feldman, 2021) did not mention IVIG as a therapeutic option for diabetic polyneuropathy.
Idiopathic Progressive Neuropathy
Liu et al (2018) noted that small-fiber polyneuropathy (SFPN) has various underlying causes, including associations with systemic autoimmune conditions. These researchers have proposed a new cause; small-fiber-targeting autoimmune diseases akin to Guillain-Barre and chronic inflammatory demyelinating polyneuropathy (CIDP). There are no treatment studies yet for this ‘apparently autoimmune SFPN’ (aaSFPN), but intravenous immunoglobulin (IVIG), 1st-line for Guillain-Barre and CIDP, is prescribed off-label for aaSFPN despite very high cost. These investigators conducted the first systematic evaluation of IVIG’s effectiveness for aaSFPN. With IRB approval, these researchers extracted all available paper and electronic medical records of qualifying patients. Inclusion required having objectively confirmed SFPN, autoimmune attribution and other potential causes excluded. IVIG needed to have been dosed at greater than or equal to 1 g/kg/4 weeks for greater than or equal to 3 months. These investigators chose 2 primary outcomes -- changes in composite autonomic function testing (AFT) reports of SFPN and in ratings of pain severity -- to capture objective as well as patient-prioritized outcomes. Among all 55 eligible patients, SFPN had been confirmed by 3/3 nerve biopsies, 62 % of skin biopsies, and 89 % of composite AFT. Evidence of autoimmunity included 27 % of patients having systemic autoimmune disorders, 20 % having prior organ-specific autoimmune illnesses and 80 % having greater than or equal to 1/5 abnormal blood-test markers associated with autoimmunity. A total of 73 % had apparent small-fiber-restricted autoimmunity. IVIG treatment duration averaged 28 ± 25 months. The proportion of AFTs interpreted as indicating SFPN dropped from 89 % at baseline to 55 % (p ⩽ 0.001). Sweat production normalized (p = 0.039) and the other 4 domains all trended toward improvement. Among patients with pre-treatment pain greater than or equal to 3/10, severity averaging 6.3 ± 1.7 dropped to 5.2 ± 2.1 (p = 0.007). Overall, 74 % of patients rated themselves "improved" and their neurologists labeled 77 % as "IVIG responders"; 16 % entered remissions that were sustained after IVIG withdrawal. All adverse events (AEs) were expected; most were typical infusion reactions. The 2 moderate complications (3.6 %) were vein thromboses not requiring discontinuation. The 1 severe event (1.8 %), hemolytic anemia, remitted after IVIG discontinuation. The authors concluded that these findings provided Class IV, real-world, proof-of-concept evidence suggesting that IVIG is safe and effective for rigorously selected SFPN patients with apparent autoimmune causality. They provided rationale for prospective trials, inform trial design and indirectly support the discovery of small-fiber-targeting autoimmune/inflammatory illnesses. These researchers stated that this study helped them develop interim case definitions and treatment guidelines that may be useful clinically.
This study’s main drawback was that it was a retrospective study that provided only Class IV evidence. An inherent limitation in "real-world" studies is variation in dosing and assessment parameters. In this trial, the initial target dose was 2.0 g/kg/4 weeks, as in all 5 major placebo-controlled trials of IVIG for chronic inflammatory demyelinating polyneuropathy (CIDP). These researchers and others found it more efficient to trial the highest recommended dose, and then titrated downwards, rather than to try low doses that, if ineffective, often engender retrials of higher doses. Other potential contributors to dosing variability included potentially inaccurate patient weights, rounding doses and dose individualizations for reasons including tolerability. The actual initial doses, all 1.3 to 2.0 g/kg/4 weeks, were within the range used in clinical trials for CIDP, and similar to the mean 1.4 ± 0.6 g/kg/4.3 weeks dose optimal for CIDP and multifocal motor mononeuropathy.
Hematophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome
An UpToDate review(McClain, et al., 2017) states that IVIG may be indicated for persons with hematophagocytic lymphohistiocytosis (HLH) if they develop an underlying immunodeficiency and hypogammaglobulinemia. UpToDate explains that macrophage activation syndrome (MAS) is a form of HLH in patients with juvenile idiopathic arthritis and other rheumatologic conditions. "For those with underlying immunodeficiency and hypogammaglobulinemia, or those who develop hypogammaglobulinemia from HLH-specific therapy, we give intravenous immune globulin (IVIG) as well, at a dose of 500 mg/kg."
Boom and colleagues (2015) stated that macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. In a systematic review, these researchers evaluated currently available literature on diagnostic criteria for MAS in sJIA and provided an overview of possible biomarkers for diagnosis, disease activity and therapeutic response and recent advances in treatment. A systematic literature search was performed in Medline, Embase and Cochrane. A total of 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least 2 independent experts for validity and level of evidence according to EULAR guidelines. A total of 27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium led by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment came from case-series studies. High-dose corticosteroids with or without cyclosporine A were frequently reported as 1st-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra. The authors concluded that MAS in sJIA appeared to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence-based medicine.
Status Epilepticus
Zeiler and colleagues (2017) performed a scoping systematic review of the literature on the use of IVIG for refractory status epilepticus (RSE) in adults. Articles from Medline, BIOSIS, Embase, Global Health, Healthstar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform, clinicaltrials.gov (inception to May 2016), reference lists of relevant articles, and gray literature were searched. The strength of evidence was adjudicated using both the Oxford and GRADE methodology by 2 independent reviewers. A total of 24 original articles were identified; 33 adult patients were described as receiving IVIG for RSE. Seizure reduction/control with IVIG occurred in 15 of the 33 patients (45.4 %), with 1 (3.0 %) and 14 (42.4 %) displaying partial response (PR) and complete responses (CRs), respectively. No adverse events (AEs) were recorded. The authors concluded that Oxford level 4, GRADE D evidence exists to suggest an unclear impact of IVIG therapy in adult RSE. These investigators stated that routine use of IVIG in adult RSE cannot be recommended at this time.
Hypogammaglobulinemia from Chimeric Antigen Receptor T (CAR-T) Therapy
Hypogammaglobulinemia and agammaglobulinemia (IgG) related to B-cell aplasia can occur in patients with a complete remission (CR) after tisagenlecleucel (Kymriah) infusion. Hypogammaglobulinemia was reported in 43% of patients treated with KYMRIAH for r/r ALL and 14% of patients with r/r DLBCL. Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement standard guidelines.
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with YESCARTA. In Study 1, hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment with axicabtagene ciloleucel (Yescarta) and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement.
Neonatal Hyperbilirubinemia
Zwiers et al (2018) stated exchange transfusion and phototherapy have traditionally been used to treat jaundice and avoid the associated neurological complications. Because of the risks and burdens of exchange transfusion, intravenous immunoglobulin (IVIg) has been suggested as an alternative therapy for alloimmune hemolytic disease of the newborn (HDN) to reduce the need for exchange transfusion. The objectives of this review were to assess the effect and complications of IVIg in newborn infants with alloimmune HDN on the need for and number of exchange transfusions. The authors performed electronic searches of CENTRAL, PubMed, Embase (Ovid), Web of Science, CINAHL (EBSCOhost), Academic Search Premier, and the trial registers ClinicalTrials.gov and controlled-trials.com in May 2017. The authors also searched reference lists of included and excluded trials and relevant reviews for further relevant studies. The authors considered all randomized and quasi-randomized controlled trials of IVIg in the treatment of alloimmune HDN. Trials must have used predefined criteria for the use of IVIg and exchange transfusion therapy to be included. The authors used the standard methods of Cochrane and its Neonatal Review Group. The authors assessed studies for inclusion and two review authors independently assessed quality and extracted data. The authors discussed any differences of opinion to reach consensus. The authors contacted investigators for additional or missing information. The authors calculated risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) for categorical outcomes. The authors calculated mean difference (MD) for continuous variables. The authors used GRADE criteria to assess the risk of bias for major outcomes and to summarize the level of evidence. Nine studies with 658 infants fulfilled the inclusion criteria. Term and preterm infants with Rh or ABO (or both) incompatibility were included. The use of exchange transfusion decreased significantly in the immunoglobulin treated group (typical RR 0.35, 95% CI 0.25 to 0.49; typical RD -0.22, 95% CI -0.27 to -0.16; NNTB 5). The mean number of exchange transfusions per infant was also significantly lower in the immunoglobulin treated group (MD -0.34, 95% CI -0.50 to -0.17). However, sensitivity analysis by risk of bias showed that in the only two studies in which the treatment was masked by use of a placebo and outcome assessment was blinded, the results differed; there was no difference in the need for exchange transfusions (RR 0.98, 95% CI 0.48 to 1.98) or number of exchange transfusions (MD -0.04, 95% CI -0.18 to 0.10). Two studies assessed long-term outcomes and found no cases of kernicterus, deafness or cerebral palsy. The authors concluded that although overall results show a significant reduction in the need for exchange transfusion in infants treated with IVIg, the applicability of the results is limited because of low to very low quality of evidence. Furthermore, the two studies at lowest risk of bias show no benefit of IVIg in reducing the need for and number of exchange transfusions. Based on these results, the authors have insufficient confidence in the effect estimate for benefit of IVIg to make even a weak recommendation for the use of IVIg for the treatment of alloimmune HDN. Further studies are needed before the use of IVIg for the treatment of alloimmune HDN can be recommended, and should include blinding of the intervention by use of a placebo as well as sufficient sample size to assess the potential for serious adverse effects.
Ree et al (2017) stated hemolytic disease of the fetus and newborn (HDFN) occurs when fetal and neonatal erythroid cells are destroyed by maternal erythrocyte alloantibodies, it leads to anemia and hydrops in the fetus, and hyperbilirubinemia and kernicterus in the newborn. Postnatal care consists of intensive phototherapy and exchange transfusions to treat severe hyperbilirubinemia and top-up transfusions to treat early and late anemia. Other postnatal complications have been reported such as thrombocytopenia, iron overload and cholestasis requiring specific management. Areas covered: This review focusses on the current neonatal management and outcome of hemolytic disease and discusses postnatal treatment options as well as literature on long-term neurodevelopmental outcome. Expert commentary: Despite major advances in neonatal management, multiple issues have to be addressed to optimize postnatal management and completely eradicate kernicterus. Except for strict adherence to guidelines, improvement could be achieved by clarifying the epidemiology and pathophysiology of HDFN. Several pharmacotherapeutic agents should be further researched as alternative treatment options in hyperbilirubinemia, including immunoglobulins, albumin, phenobarbital, metalloporphyrins, zinc, clofibrate and prebiotics. Larger trials are warranted to evaluate EPO, folate and vitamin E in neonates. Long-term follow-up studies are needed in HDFN, especially on thrombocytopenia, iron overload and cholestasis.
Treatment of Pyoderma Gangrenosum
Herberger and colleagues (2019) noted that corticosteroids and cyclosporine A are frequently ineffective as 1st-line therapies in the treatment of pyoderma gangrenosum (PG) and associated with a number of AEs. In a retrospective, dual-center, cohort study, these investigators examined the safety and effectiveness of biologics and IVIGs in the treatment of PG. total of 52 patients (mean age of 58.4 years) with 75 wound episodes (mean wound size of 53.2 cm²) were included in the study. Overall, 92.3 % of patients initially received corticosteroids (CSs; 48/52); 51.9 % cyclosporine A (CSA; 27/52). In 275 therapeutic attempts, complete remission or improvement were achieved in 63.6 % (21/33) of patients on infliximab; 57.1 % (16/28) on adalimumab; 71.4 % (5/7) on etanercept; 66.6 % (6/9) on ustekinumab, and 66.7 % (10/15) of patients who were given IVIGs. That figure was 48.8 % (38/78) for those treated with CSs and 20.0 % (7/35) for individuals on CSA. On average, AEs occurred in 18.5 % (15/81) of cases treated with biologics in 20 % (3/15) of patients receiving IVIGs, in 40 % (14/35) of individuals on CSA and in 10.4 % of those treated with CSs (5/48). The authors concluded that the present retrospective analysis suggested that both biologics (especially TNF-alpha antagonists) and IVIGs are well-tolerated and safe options in the treatment of PG. Moreover, these researchers stated that data from prospective comparative studies are highly desirable.
Treatment of PANDAS and PANS
Sigra and colleagues (2018) stated that PANDAS are a subtype of acute-onset OCD thought to be caused by an autoimmune response to group A streptococcal infection. Based on this proposed pathophysiology, alternative treatments for acute-onset OCD have been introduced, including antibiotics and immunomodulatory interventions. However, the literature on treatment of PANDAS is diverse, and clinical consensus regarding optimal treatment strategy is lacking. These investigators conducted a systematic review of articles in PubMed, Cochrane Library, and Scopus that addressed treatment for PANDAS and related disorders. A total of 12 research studies involving the following treatments met inclusion criteria: penicillin, azithromycin, IVIG, PE, tonsillectomy, cognitive behavior therapy, NSAID and corticosteroids. In addition, 65 case reports in which patients received immunomodulatory treatments, antibiotics, and/or psychotropics were identified. These researchers noted that IVIG has been described in multiple case reports and case series. Results from the self-reported survey study provided some support for IVIG being perceived as an effective treatment for PANS; IVIG has been tested in 2 double-blind RCTs, with the higher quality study indicating low support. Therefore, the evidence for using IVIG is inconclusive. The authors concluded that rigorously conducted research regarding treatments for PANDAS is scarce, and published studies have a high risk of bias. They stated that further research is needed in which promising treatment strategies for PANDAS and other variants of OCD with proposed autoimmune etiology are rigorously examined.reatment of Anti-Synthetase Syndrome
Spath and associates (2004) determined the response to treatment and the long-term outcome of patients with the anti-synthetase syndrome (ASS) associated with anti-Jo-1-antibodies. A total of 12 patients with histologically proven myositis and anti-Jo-1-autoantibodies were evaluated over a mean follow-up period of 66.4 months. In all patients neuromuscular function tests, EMG examinations, pulmonary function tests and high-resolution-computed tomography of the lungs were performed regularly. Muscle function improved in all patients with treatment, and a complete clinical response was achieved in 5 patients. Pulmonary function worsened in 1 patient, who died from respiratory failure, but normalized in 4 patients. Arthropathy progressed despite improvement of myositis and pulmonary status in 2 patients. Discontinuation of treatment was facilitated in 1 patient, although long-term therapy was needed in 10 patients. In 2 patients with refractory disease, treatment with IVIG was successful. Severe side effects of treatment occurred in 7 patients and overall mortality rate was 1 of 12 (8 %). The authors concluded that ASS associated with anti-Jo-1-antibodies required long-term immunosuppressive therapy in most patients. Whereas a complete clinical response of muscular symptoms was frequent, continued deterioration of the pulmonary system may occur despite immunosuppressive treatment, and may lead to fatal outcome. An inter-disciplinary therapeutic approach is necessary for best possible results in these patients.
Marie and colleagues (2013) assessed the outcome, including functional course, in anti-Jo1 positive patients with ASS, and determined predictive parameters of poor outcome in these patients. The medical records of 86 consecutive anti-Jo1 patients with ASS were reviewed in 4 academic centers; 13 patients (15.1 %) achieved remission of ASS, whereas 55 (63.9 %) improved, and 18 (20.9 %) deteriorated in their clinical status. Both steroid and cytotoxic drugs could be discontinued in only 4.7 % of patients; ASS was associated with decreased quality of life (QOL) at long-term follow-up: only 69.2 % of patients considered to be in remission experienced a return to previous normal activities; and 24.7 % of other patients with non-remitting ASS still had a marked reduction of activities (as shown by the disability scale of the Health Assessment Questionnaire). Decreased QOL was further due to calcinosis cutis (8.1 %) and adverse effects of steroid therapy (36 %). Factors associated with ASS deterioration were older age, pulmonary and esophageal involvement, calcinosis cutis and cancer. Higher anti-Jo1 levels were further associated with disease severity in ASS patients. The authors concluded that present study showed high morbidity related to ASS. Furthermore, they suggested that patients with predictive factors of ASS deterioration may require more aggressive therapy. These findings also suggested that in anti-Jo1 patients with severe esophageal manifestations, combined high dose steroids and IVIGs might be proposed as the 1st-line therapy. Finally, as cancer occurred in 14 % of anti-Jo1 patients, these findings underscored that the search for cancer should be performed in these patients.
Martino et al (2009) stated that despite their empirical use in community settings, there is still a lack of conclusive, evidence-based data regarding the usefulness of antibiotic and immuno-modulatory treatments in children with PANDAS.
Marconi et al (2009) stated that the use of treatment strategies, such as therapeutic plasmapheresis or IVIG, has been proposed to explain the autoimmune process responsible for the pathogenesis of PANDAS. Moreover, they stated that further research is still necessary in order to understand the role of streptococcal infection in the pathogenesis of PANDAS.
Shulman (2009) noted that the relationship between obsessive-compulsive disorder (OCD) or tics/Tourette's syndrome in childhood to antecedent group A streptococci (GAS) is unclear. One recent prospective cohort study found that more than 85 % of clinical exacerbations in OCD/tic behavior in patients who met criteria for PANDAS had no relationship to GAS infection. Another study found no correlation between clinical exacerbations and changes in a variety of markers of brain autoimmunity, the proposed pathogenesis of PANDAS. A third recent study concluded that, compared with specialty clinic diagnoses, patients diagnosed with tics or Tourette's by physicians in the community were significantly more likely to be diagnosed with PANDAS without meeting the proposed criteria, most lacked supporting laboratory evidence of GAS infection, and they were more likely to be treated with unjustified short-term to chronic antibiotic and/or immuno-modulatory therapy.
Tan et al (2012) posed the question "I have heard about children who have tic disorders that seem to be exacerbated by group A β-hemolytic streptococcal infection. Should children presenting with this phenomenon receive treatment with antibiotics, receive prophylactic treatment, or use immunomodulators to treat the symptoms?" They noted the answer to be: "Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) constitute a condition that includes neuropsychiatric symptoms, mainly obsessive-compulsive disorder or tic disorders, temporally associated with an immune-mediated response to streptococcal infections. The actual existence of PANDAS as a unique clinical entity is still up for debate, as a temporal association between group A β-hemolytic streptococcal infections and symptom exacerbations has been difficult to prove thus far. Based on only a few studies, positive results have been found using antibiotic prophylaxis and immunomodulatory therapy in children with PANDAS. At this time, however, evidence does not support a recommendation for long-term antibiotic prophylaxis or immunomodulatory therapy."
An UpToDate review on "PANDAS: Pediatric autoimmune neuropsychiatric disorder associated with group A streptococci" (Pichichero, 2021) states that "Routine administration of immunomodulatory therapy (e.g., glucocorticoids, plasma exchange, intravenous immunoglobulin [IVIG]) is not indicated for children who meet PANDAS criteria".
Treatment of Bortezomib-Induced Peripheral Neurotoxicity
Meregalli and colleagues (2018) stated that chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe adverse effect in patients receiving anti-tumor agents, and no effective treatment is available. Although the mechanisms responsible for the development of CIPN are poorly understood, recent findings make neuro-inflammation an attractive target to be investigated, particularly when neuropathic pain is a prominent feature such as after bortezomib administration. These researchers evaluated the effect of IVIG in the treatment of chronic CIPN. The related neuro-immune aspects were examined in a well-characterized rat model of bortezomib-induced peripheral neurotoxicity (BIPN). After determination of a suitable schedule based on a preliminary pharmacokinetic pilot study, female Wistar rats were treated with IVIG 1 g/kg every 2 weeks. IVIG treatment was started at the beginning of bortezomib administration ("preventive" schedule), or once BIPN was already ensued after 4 weeks of treatment ("therapeutic" schedule). Neurophysiological and behavioral studies were performed to assess the extent of painful peripheral neurotoxicity induced by bortezomib, and these functional assessments were completed by pathologic examination of peripheral nerves and intra-epidermal nerve fiber (IENF) quantification. The role of the innate immune response in BIPN was examined by immunochemistry characterization of macrophage infiltration in peripheral nerves. Both schedules of IVIG administration were able to significantly reduce bortezomib-induced heat and mechanical allodynia. Although these changes were not evidenced at the neurophysiological examination of peripheral nerves, the behavioral effects were paralleled in the animals treated with the preventive schedule by reduced axonopathy in peripheral nerves and significant protection from loss of IENF. Moreover, IVIG was very effective in reducing infiltration in peripheral nerves of macrophages with the M1, pro-inflammatory phenotype. The authors concluded that these findings suggested a prominent role of neuro-inflammation in BIPN and that IVIG might be considered as a possible safe and effective therapeutic option preventing M1 macrophage infiltration. However, since neuropathic pain is also frequent in other CIPN types, it also indicated the need for further investigation in other forms of CIPN.
Treatment of Hand-Foot-Mouth Disease
Zhang and associates (2018) noted that in contrast to the guidelines of World Health Organization (WHO) and United States-Centers for Disease Control and prevention (US-CDC), the Chinese national guidelines recommend the use of steroids, IVIG, or traditional Chinese herbs (TCHs) in hand-foot-mouth disease (HFMD) management. Their use and therapeutic efficacies are, however, unclear. These investigators described their use in and the clinical outcomes of hospitalized HFMD cases. They carried out a retrospective review of hospital medical records for HFMD cases during 2008 to 2016 in a medical school-affiliated tertiary hospital in Shantou, Guangdong, China. Hospitalized children with the discharge diagnosis of HFMD (n = 3,778), comprising mild (58.4 %), severe (41.5 %), and very severe (0.1 %) cases, were enrolled in the study. Steroids, IVIG, and antiviral TCH Lan-Qin were respectively prescribed in 60.5, 37.1, and 71.0 % of cases. Most cases (99.8 %) recovered and 6 died. Recovery rate was lower with the use of IVIG and higher with Lan-Qin (alone or in combination with steroid) in the mild cases (p < 0.05). Longer hospital stay was observed with steroid/IVIG with or without Lan-Qin in the severe cases (p < 0.05). The authors concluded that this 9-year retrospective review showed an increase in the incidence of HFMD as well as the use of steroids, IVIG, and TCH over time; no significant advantage of using steroids and IVIG, either alone or in combination, in the management of mild HFMD cases, and a higher recovery rate in mild HFMD cases with the use of antiviral TCH (Lan-Qin). They stated that these findings need verification in a larger prospect study with cases from hospitals in other regions of China. Lan-Qin efficacy should be evaluated in randomized trials. Meanwhile, caution should be exercised in the extensive use of steroids and IVIG in HFMD management.
The authors concluded that this study had several drawbacks. First, high-risk HFMD mild cases were neither documented in the medical records nor identified by this review, disenabling these investigators to perform independent outcome analysis of this group. Second, the outcome of the self-discharged patients was not known as follow-up information was not available. Lastly, assessment of outcomes (e.g., the time of fever clearance or rash disappearance and the rate of severe HFMD development) with the use of steroid, IVIG, or TCHs was not possible due to lack of data in the medical records.
Furthermore, an UpToDate review on "Hand, foot, and mouth disease and herpangina" (Romero, 2020) does not mention IVIG as a therapeutic option.
Jiao and colleagues (2019) conducted a meta-analysis of evidence from RCTs of different doses of IVIG in children with severe HFMD to provide the scientific basis for clinical practice. These researchers carried out a search of PubMed-Medline, CNKI, Wanfang, and VIP database (until June 30, 2017) and Software RevMan5.3 was used to evaluate the effect of different doses of IVIG on HFMD in RCTs. They used random effects models (or fixed effects models) and generic inverse variance methods to process quantitative data, followed by a leave-one-out method for sensitivity analysis. From a total of 420 entries identified via searches, 8 RCTs involving 1,450 patients were included in the final analysis. The results of the meta-analysis showed that compared with conventional therapy alone, conventional therapy combined with IVIG had shorter fever clearance time, shorter rash regression time and shorter clinical cure time. Subgroup analyses showed that the high-dose group (1g/kg per day) had shorter fever clearance time (p < 0.05), shorter rash regression (p < 0.05), shorter remission time of neurological symptoms (p < 0.05), but longer clinical cure time (p > 0.05). The authors concluded that the high-dose group had a better prognosis, however, the advantages and disadvantages should be carefully considered when deciding the doses in the treatment of severe HFMD. However, these researchers stated that more high quality studies are needed to verify these findings.
The authors stated that this meta-analysis had 2 main drawbacks. First, there were only 8 studies included in the analysis, which may have led to publication-bias; thus reducing the validity of the conclusion. Second, in 8 studies included in the study, only 1 study used the random number table method, while other studies did not mention the grouping method, and there were no description of the specific situation of allocation concealment and blinding in all studies; thus, resulting in selection bias, measurement bias, and information bias.
Treatment of Narcolepsy
Ruppert and associates (2018) stated that narcolepsy type 1 is a rare disabling sleep disorder mainly characterized by excessive daytime sleepiness and cataplexy, an emotion-triggered sudden loss of muscle tone. Patients have a selective degeneration of hypocretin-producing neurons in the dorsolateral posterior hypothalamus with growing evidence supporting the hypothesis of an autoimmune mechanism. Few case studies that reported IVIG suggested the efficacy of IVIG when administered early after disease onset, but the results are controversial. In a study of 3 retrospective cases, IVIG cycles were initiated within 1 to 4 months after cataplexy onset in a 27-year old man, a 10-year old girl, and a 7-year old boy, all with early onset typical narcolepsy type 1. Efficacy of treatment (3 IVIG cycles of 1 g/kg administered at 4-week intervals) was evaluated based on clinical, polysomnographic, and multiple sleep latency test (mean latency and SOREM) follow-up; 2 patients reported decreased cataplexy frequency and ameliorated daytime sleepiness, but no significant amelioration of polysomnographic parameters was observed. The authors concluded that given the possibility of spontaneous improvement of cataplexy frequency with self-behavioral adjustments, these observations need to be confirmed by larger controlled studies. These researchers stated that based on the findings of this study and current literature, proof-of-concept is still missing; thus prohibiting the consideration of IVIG as an efficient therapeutic option.
Treatment of New Onset Dilated Cardiomyopathy
Heidendael and colleagues (2018) noted that dilated cardiomyopathy is a rare but serious disorder in children. No effective diagnostic or therapeutic tools are readily available. In a retrospective cohort study, these researchers examined the efficacy of IVIGs in children with new onset dilated cardiomyopathy. A total of 94 children with new onset dilated cardiomyopathy were followed during a median period of 33 months. All patients with secondary dilated cardiomyopathy (e.g., genetic, auto-immune or structural defects) were excluded from this study. Viral tests were performed in all patients and 18 (19 %) children met the criteria for the diagnosis "probable or definite viral myocarditis"; IVIGs were administered to 21 (22 %) patients. Overall transplant-free survival was 75 % in 5 years and did not differ between therapeutic groups. The treatment was associated with a higher recovery rate within 5 years, compared with non-treated children (70 versus 43 %, log rank = 0.045). After correction for possible confounders the hazard ratio (HR) for recovery with IVIGs was not significant (HR: 2.1; 95 % CI: 1.0 to 4.6; p = 0.056). Administration of IVIGs resulted in a greater improvement in the shortening fraction of the left ventricle. The authors concluded that in this population of children with new onset dilated cardiomyopathy, of either viral or idiopathic origin, IVIGs were administered to a minority of the patients and did not influence transplant-free survival, but were associated with better improvement of systolic left ventricular function and with better recovery. These investigators stated that these findings support the concept that children with new onset dilated cardiomyopathy might benefit from IVIGs.
Treatment of Oral Lichen Planus
Bender and colleagues (2018) stated that erosive oral lichen planus (OLP) is, at times, extremely difficult to treat and has a major impact on patients' quality of life (QOL). There are only limited therapeutic options, such as topical and systemic glucocorticoids, retinoids, and immuno-suppressants with considerable side effects and limited efficacy upon chronic use. In a clinical trial, these researchers examined the efficacy of adjuvant IVIG (2 g/kg/monthly cycle) in addition to the oral retinoid, acitretin, in 3 patients with refractory OLP over a period of 2 to 6 months. The efficacy of adjuvant IVIG treatment was evaluated using the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS), which measures both extent of mucosal lesions and functional sequelae. The 3 OLP patients showed mixed responses to adjuvant IVIG treatment, ranging from therapeutic efficacy to a lack of response to IVIG. The authors concluded that in light of the observed therapeutic responses and a lack of good therapeutic options, adjuvant IVIG, although costly, warrants further investigation as a therapeutic option for OLP.
Treatment of Rash after Embryo Transfer
Gleicher and Barad (2011) noted that pregnancy represents a semi-allograft, subject to similar immune responses as allogeneic organ transplants. Tolerance of pregnancy appears best with maximal class II HLA heterogeneity between mother and father, while compatibilities are associated with increased pregnancy loss and maternal autoimmunity. Tolerance abnormalities often involve skin reactions. Abnormalities in tolerance of the fetal graft may do the same. In a prospective case-series study, these researchers defined the characteristics of a newly described dermatosis in very early pregnancy. A total of 7 couples/12 clinical episodes were included in this trial. Dermatosis was observed in 7 out of 285 women undergoing in-vitro fertilization (IVF; 2.5 %; 95 % CI: 0.66 to 4.26 %), and in 12 out of 277 total IVF cycles reaching embryo transfer (4.3 %; 95 % CI: 1.93 to 6.73 %). Prior to IVF all women reported autoimmune clinically significant allergies. All but 1 couple demonstrated class II HLA compatibility; 2 of 4 pregnancies miscarried. All rashes erupted within days from embryo implantation. The rash in all 7 patients improved with increasing prednisone dosage and, indeed, in 1 patient increased in severity after prednisone had been tapered. The authors concluded that the "implantation rash" reported in this study was uncommon but not rare. It may be the consequence of abnormal maternal immune responses to embryo implantation in women with prior immune activation, associated with class II HLA compatibility between parents. Moreover, they stated that further prospective studies are needed to better-define this condition.
The authors concluded that these findings were preliminary in nature and only observational. To confirm the reported findings of a new dermatosis of very early pregnancy and its proposed pathophysiology, further cases need to be prospectively accumulated, demonstrating an association with HLA class II overlaps between mother and father as well as maternal autoimmunity. Most importantly, however, skin biopsies will have to be performed to demonstrate similarities with reported skin lesions in allogeneic graft-versus-host disease (GVHD) and graft rejection.
Currently, there is a lack of evidence regarding the use of IVIG in the treatment of implantation rash/rash after embryo transfer.
Lambert-Eaton Syndrome
In people with Lambert-Eaton Syndrome (LEMS), the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. The prevalence of LEMS is estimated to be three per million individuals worldwide.
On November 28, 2018, the U.S. Food and Drug Administration (FDA) approved Firdapse (amifampridine) tablets for the treatment of LEMS in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS. Amifampridine phosphate is described chemically as 3,4-diaminopyridine phosphate. The efficacy of Firdapse was studied in two clinical trials that together included 64 adult patients who received Firdapse or placebo. The studies measured the Quantitative Myasthenia Gravis score (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression (a seven-point scale on which patients rated their overall impression of the effects of the study treatment on their physical well-being). For both measures, the patients receiving Firdapse experienced a greater benefit than those on placebo. The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms. Seizures have been observed in patients without a history of seizures. Patients should inform their health care provider immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.
Treatment of Relapsing Remitting Multiple Sclerosis (MS)
An UpToDate review on "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects" (Olek and Mowry, 2021) states although data are equivocal, there is no compelling evidence that intravenous immune globulin (IVIG) is effective for patients with RRMS. Some, but not all early clinical trials reported beneficial effects for IVIG in RRMS. However, these trials generally involved small numbers of patients, lacked complete data on clinical and MRI outcomes, or used questionable methodology. A later multicenter placebo-controlled trial of 127 patients with RRMS found that IVIG treatment conferred no benefit for reducing relapses or new lesions on MRI.
Treatment of Toxic Epidermal Necrolysis (TEN) and Steven-Johnson Syndrome (SJS)
In an UpToDate review on Stevens-Johnson syndrome and toxic epidermal necrolysis (High, 2021), the author states data surrounding the use of IVIG for SJS/TEN are limited and conflicting and suggests not using intravenous immune globulin (IVIG) for SJS/TEN (Grade 2C) because no clear survival advantage has been found for patients with SJS/TEN treated with IVIG in several meta-analyses.
Intramuscular Immunoglobulins (e.g., GamaSTAN S/D)
An UpToDate review on subcutaneous and intramuscular immune globulin therapy (Jolles, Hons, and Hons, 2020) states intramuscular immune globulin (IMIG) for immunodeficiency has few advantages compared with SC and IV preparations and is rarely used. Injections are painful, the amount that can be injected is limited, there is risk of local tissue injury (such as nerve damage), and there is a higher risk of reactions. It is also not possible, in practice, to attain serum IgG levels in the normal range using the IM route. Because IMIG is rarely used for chronic therapy, there have been no studies comparing the efficacy of IM administration with other routes for more than 20 years. IMIG injections are generally used only in single doses to provide short-term protection against infection such as a local outbreak of measles or another infectious disease against which certain individuals have not been immunized, to prevent hepatitis A infection in individuals traveling to endemic areas, and for prophylaxis against chicken pox in unimmunized high-risk individuals, such as immunocompromised children or in first trimester pregnant women, to prevent in utero varicella.
Hanson et al (1983) stated hypogammaglobulinemia patients, who seem to be more numerous than previously known, have an unacceptable diagnostic delay of 12 years. They often get insufficient Ig prophylaxis, frequently due to the side effects caused by the im administration. A new Ig preparation for IV use has been utilized, which is much more acceptable to the patients, causing very few side effects. In contrast to im preparations, IV immunoglobulin can be used at high doses, quickly normalizing the patient's serum IgG level, and seems to permit longer intervals between infusions during long-term prophylaxis.
Autoimmune Gastrointestinal Dysmotility, including Autoimmune Gastroparesis
Katz et al (2011) stated that intravenous Immunoglobulins (IVIG) are administered both as replacement therapy for certain immunodeficiencies and as immunomodulatory therapy for some autoimmune diseases. While the treatment with IVIG is approved in only a few autoimmune diseases, the number of off-label indications is increasing. The varied mechanisms by which IVIG attains its beneficial effect are diverse. There is much evidence for the beneficial and safety profile for IVIG in low- as well as high-dose protocols. Patients prone to develop thrombotic events should be advised about the risk of IVIG therapy especially at high doses. The authors updated the mechanisms of action of IVIG as well as recent off-label indications.
Flanagan et al (2014) noted that chronic gastro-intestinal (GI) dysmotility greatly impacts the quality of life (QOL); and therapeutic options are limited and generally symptomatic. Neural autoimmunity is an under-recognized etiology. These researchers evaluated immunotherapy as an aid to diagnosing autoimmune GI dysmotility (AGID). A total of 23 subjects evaluated at the Mayo Clinic for suspected AGID (August 2006 to February 2014) fulfilled the following criteria:- prominent symptoms of GI dysmotility with abnormalities on scintigraphy-manometry;
- serological evidence or personal/family history of autoimmune disease;
- treated by immunotherapy on a trial basis, 6 to 12 weeks (IVIG, n = 16; or methylprednisolone, n = 5; or both, n = 2).
Response was defined subjectively (symptomatic improvement) and objectively (GI scintigraphy/manometry studies). Symptoms at presentation: constipation, 18/23; nausea or vomiting, 18/23; weight loss, 17/23; bloating, 13/23; and early satiety, 4/23; 13 patients had personal/family history of autoimmunity; 16 had neural autoantibodies and 19 had extra-intestinal autonomic testing abnormalities. Cancer was detected in 3 patients. Pre-immunotherapy scintigraphy revealed slowed transit (19/21 evaluated; gastric, n = 11; small bowel, n = 12; colonic, n = 11); manometry studies were abnormal in 7/8. Post-immunotherapy, 17 (74 %) had improvement (both symptomatic and scintigraphic, n = 5; symptomatic alone, n = 8; scintigraphic alone, n = 4); 9 responders re-evaluated had scintigraphic evidence of improvement. The majority of responders who were re-evaluated had improvement in autonomic testing (6 of 7) or manometry (2 of 2). The authors concluded that this proof-of-principle study showed the importance of considering an autoimmune basis for idiopathic gastrointestinal dysmotility and supports the utility of a diagnostic trial of immunotherapy.
The authors stated that this study had several drawbacks. The lack of a placebo-treated group and small numbers (n = 23) made it difficult to determine the natural course of AGID and limited the assessment of statistically significance in this study. This trial was also limited by short follow-up (6 to 12 weeks). The selection of immunotherapy modality was based on patient preference, insurance coverage, neural autoantibody type and the diagnosis of an underlying cancer. Steroid-induced improvement in sense of well-being and placebo-response were potentially confounding factors when symptoms of AGID and dysautonomia were mainly subjective. Although these researchers could not exclude the possibility that corticosteroids or IVIG may influence GI motility by a mechanism unrelated to autoimmunity, the observations they had documented support the autoimmune hypothesis. They stated that there is a need for randomized placebo controlled double-blind trials in AGID.
Soota et al (2016) stated that patients with generalized autoimmune dysautonomia may also present with gastroparesis. Immune dysfunction in such patients can be evaluated using antibodies to glutamic acid decarboxylase (GAD) and full thickness biopsy of stomach. In a retrospective chart review, these investigators employed immunotherapy for treatment of drug- and gastric electrical stimulation (GES)-resistant gastroparetic patients with evidence of neuroinflammation on full thickness gastric biopsy and had positive GAD65 autoantibodies. This review included 11 female patients with drug- and device-resistant gastroparesis. Patients were treated for a total of 8 to 12 weeks with either IVIG, or combined mycophenolate mofetil (MM) and methylprednisolone, or only MM. Patients were excluded if they had previous side effects from steroid therapy, low scores on dual-energy X-ray absorptiometry (DEXA) scan results, immune-compromised conditions with infections like tuberculosis and zoster. Symptoms of nausea, vomiting, abdominal pain, early satiety/anorexia, bloating and total symptom score (TSS) as reported by the patients were recorded before and after the treatment at a follow-up visit 2 to 16 weeks after initiation of therapy. Maximum symptom improvement was observed n patients treated with IVIG (67 %); 6 patients (55 %) had improvement in vomiting, whereas 5 patients (45 %) had improvements in nausea, abdominal pain and bloating. The authors concluded that immunomodulatory therapy showed positive outcomes in improving vomiting symptom in some gastroparetic patients who have co-existing positive autoimmune profiles. These researchers stated that these preliminary findings suggested the need for further investigations in immunotherapy targeted to patients with gastroparetic symptoms refractory to approved drug and device therapies. They stated that to further validate the potential clinical benefit, they recommended prospective evaluation of this therapy in randomized controlled and blinded trials.
Ashat et al (2018) noted that gastroparesis is a complex clinical entity; many aspects of which remain unknown. Although most patients have idiopathic, diabetic, or post-surgical gastroparesis, many are thought to have measurable neuromuscular abnormalities. Immunotherapy has recently been utilized to treat suspected AGID. In an open-label study, 14 patients with symptoms of gastroparesis (Gp) who were refractory to drug/device were selected from 443 Gp patients from 2013 to 2015 who were treated at the University of Louisville motility center. All patients underwent a structural and psychiatric evaluation along with detailed psychological and behavioral examination to rule out eating disorders. These investigators performed detailed neuromuscular evaluation and all 14 patients received at least 12 weeks of IVIG (400 mg/kg infusion weekly). Response was defined subjectively (symptomatic improvement) using standardized IDIOM score system. All 14 patients had serological evidence and/or tissue evidence of immunological abnormality. Post-IVIG therapy, there was a significant improvement in symptoms scores for nausea, vomiting, early satiety, and abdominal pain. The authors concluded that although limited by the absence of placebo group, these findings showed the role of autoimmunity and neuromuscular evaluation in patients with gastroparesis and support the utility of a diagnostic trial of immunotherapy in an effort to improve therapeutic outcomes for such patients. This was a small (n = 14) open-label study; its findings need to be validated by well-designed studies.
Idiopathic Autonomic Neuropathy
Heafield et al (1996) reported on the case of a previously healthy 23-year old man who presented with a short history of abdominal pain and diarrhea followed by blurred vision, severe postural hypotension, reduced sweating and unremitting fever. Examination revealed fixed dilated pupils, impaired sweating and postural hypotension. Clinical and neurophysiological examination showed no motor or sensory deficit. A diagnosis of idiopathic autonomic neuropathy was made. He became gravely ill with profound life-threatening hypotension and a prolonged ileus. Within 36 hours of receiving intravenous gammaglobulin (IVGG) his pupillary areflexia and severe hypotension resolved; 2 weeks later the autonomic failure recurred but again responded to treatment with IVGG; IVGG is a recognized treatment for Guillain-Barre syndrome (GBS). The authors concluded that this case report showed that IVGG was also effective in the rare pure dysautonomic variant.
Smit et al (1997) described the case of a 33-year old woman with acute idiopathic post-ganglionic panautonomic neuropathy who experienced prompt recovery of all dysautonomic symptoms after receiving high-dose intravenous immunoglobulin (IVIG) therapy. Her recovery was complete within 6 months after onset of disease. The authors concluded that this unusually rapid and complete recovery in comparison with that of historical control subjects suggested that patients with acute, severe, and widespread autonomic failure might benefit from IVIG therapy.
Yoshimaru et al (2006) described the case of acute idiopathic autonomic neuropathy (AIAN) in which IVIG proved effective. A 32-year old man was admitted with orthostatic dizziness. Fever and headache first developed 24 days earlier, and persisted for 10 days, when orthostatic dizziness developed and prevented him from walking. Hypohydrosis, constipation and impotence also developed. Neurological examinations revealed no abnormalities. Cerebrospinal fluid (CSF) obtained showed pleocytosis (26/uL) and an increased level of protein (70 mg/dL). A head-up tilt test revealed that blood pressure (BP) decreased from 120/60 mmHg when supine to 60/40 mmHg in a head-up position, and the patient complained of dizziness. Plasma noradrenaline concentration was 26 pg/ml when supine and 44 pg/ml in a head-up position. Results of MIBG cardiac scintigraphy were normal. Dizziness disappeared after initiating IVIG (0.4 g/kg/day). A head-up tilt test was performed 7 days after IVIG, revealing BPs of 106/61 mmHg when supine and 103/71 mmHg in a head-up position. The authors concluded that these results suggested that IVIG should be considered as a choice to treat early AIAN.
Zuberbuhler et al (2015) noted that sensory neuronopathies or ganglionopathies, or dorsal root ganglion disorders, represent a subgroup of peripheral nervous system (PNS) diseases, frequently associated with dysimmune or neoplastic disorders and with toxic agents. A degeneration of both central and peripheral sensory projections is present. Patients typically show early ataxia, loss of deep tendon reflexes and positive sensory symptoms present both in proximal and distal sites of the body. These researchers retrospectively studied 10 cases with a final diagnosis of sensory neuronopathy. Sensory neuropathy was the presenting symptom and the course was subacute in all cases. Paresthesias in upper limbs were a predominant manifestation (100 %). Other manifestations included: hypoesthesia (10/10), gait ataxia (8/10), autonomic symptoms (3/10) and peri-oral paresthesias (3/10). Electrophysiology showed sensory axonal neuronal pattern, with normal motor responses. Final diagnosis was acquired sensory neuronopathy in all patients, associated with Sjogren's syndrome in 2, with lupus erythematosus in 1, with rheumatoid arthritis in 1, with a cancer in 2 (paraneoplastic) and idiopathic in 4. In paraneoplastic cases, the tumor was small cell lung cancer in 1 (with positive anti-Hu antibodies), and epidermoid lung cancer in the other; 8 patients were treated with immunotherapy, high-dose intravenous methylprednisolone and/or IVIG; with poor response in 4 cases, neurologic improvement in 5, and without any change in 1 patient. The authors concluded that the findings of this study showed the typical clinical and electrophysiological pattern of subacute sensory neuronopathy, and the relevance of early treatment.
Large Granular Lymphocytic Mediated Immune Cytopenia
Schieppati et al (2015) stated that myelodysplastic Syndrome (MDS) and aplastic anemia (AA) are often associated with clinical immune manifestations. An abnormal profile of the T-cell repertoire can be detected in these patients (pts) and is thought to play a role in bone marrow (BM) insufficiency. The presence of a co-existent large granular lymphocytic (LGL) clone may exacerbate cytopenia independent of the primary disease mechanism and offers another target for therapeutic intervention. Treatment for LGL proliferation is usually immunosuppressive therapy but there is no accepted standard of care. These researchers examined the role of intravenous immunoglobulin (IVIG) as a treatment for immune-related cytopenia, i.e. Coombs negative (C-) hemolytic anemia, in a series of 12 consecutive pts with an LGL clonal proliferation documented by flow cytometry and TCR clonal rearrangements. Of the 12 cases, 9 had MDS (7 lower-risk), 1 AA with LGL liver involvement, and 1 primary myelofibrosis. One patient had suspected MDS. Overall response was assessed by MDS IWG criteria 2006. These investigators defined a hemolysis response (HLR) as complete normalization (CR) or, a greater than 50 % improvement (PR) in deviation from normal values of LDH, reticulocytes, indirect bilirubin and haptoglobin. Duration of HLR was defined as the time from onset of HLR to the time of resumption of hemolysis and loss of effect of IVIG. All pts were treated with IVIG administered at a dose of 500 mg/kg of IVIG once-weekly, in repeated cycles, with a duration ranging from 1 to 4 week(s) per cycle. Clinical characteristics: M/F ratio 10/2; median age 69 years; 10 pts had a CD3+ T-LGL and 2 had a CD3-/CD16+/CD56+ NK-LGL circulating clone. Karyotype abnormalities were non-specific; 8 pts had 1-3+ reticulin BM fibrosis; 4 had mutations in RNA-splicing genes: SF3B1 (2); SETBP1 (1); SRSF2 (1); 10 pts were evaluable for response: 8 pts responded (ORR 80 %): Hematological improvement (HI-erythroid) 8/8 (100 %); a hemolysis CR (HLR-CR) occurred in 7 (87.5 %) and hemolysis PR (HLR-PR) in 1 pt (12.5 %). Median number of cycles, follow-up, and duration of treatment were 16, 21.5 and 9.5 months (mo), respectively. The HLR-CR was durable and prolonged in 3/8 (38 %) pts; 2 of these 3 pts (67 %) did not require maintenance IVIG. Relapse from HLR occurred in 4, during infection or chemotherapy, but the response returned to the original level by shortening the intervals between administration of IVIG. One pt had relapsed after an initial response and then became refractory to IVIG. In follow-up at month 38, 75 % of pts were still responding to treatment, and 1 pt was still in remission after 46 mo. In 4 of 6 pts, corticosteroid treatment was discontinued and no longer required for chronic hemolysis, with general improvement of steroid related symptoms. Some patients had been on steroids maintenance for periods ranging from months to years. Response was more durable with continuous rather than sporadic dosing. Adverse events (AEs) were non-specific: 1 pt with self-limited isolated palpitations; 1 pt with hypertension not requiring intervention. The authors concluded that treatment with IVIG of immune cytopenia associated with LGL clones and BMF yielded durable responses in 80 % of pts. IVIG, especially at high concentrations, may enhance apoptosis, suppress proliferation of T-cells and induce immune-regulation. These researchers stated that given the relative rarity of LGL clones in MDS, further investigational studies will help define the role of IVIG and clarify the mechanism of action in this group of pts with MDS and BMF associated with LGL clones.
Rituximab-Associated Chronic CNS Enterovirus Infection
Sham and colleagues (2019) reported on the case of a 4-year old boy with pulmonary capillaritis, treated with rituximab, steroids, and azathioprine for 2 years, who presented with a 6-month history of falls and paucity of speech. Examination revealed irritability, mutism, hyperreflexia, and wide-based gait, and he had an Expanded Disability Status Scale (EDSS) score of 6.5. MRI brain revealed volume loss with extensive, bilateral T2/fluid-attenuated inversion recovery hyperintensities in the deep subcortical white matter, mesial temporal lobes, insula, globus pallidi, thalami, brainstem, and cerebellum. MRI spine revealed increased T2 signal within the central dorsal aspect of the cervical cord. Lumbar puncture showed leukocyte count of 13 × 10(6)/L (65 % lymphocytes), erythrocyte count of 1 × 10(6)/L, glucose 2.7 mmol/L, and protein 0.36 g/L. NMDAR antibody testing was negative (serum/CSF). Nasopharyngeal and broncho-alveolar lavage samples tested positive for enterovirus/rhinovirus by multiplex PCR and enterovirus was detected by RT-PCR (serum/CSF). The patient received IVIG 2 g/kg. CD19 count was 0 (normal 200 to 1,600 cells/μL), immunoglobulin G 4.0 g/L (5.4 to 13.6 g/L), immunoglobulin A 0.6 g/L (0.3 to 1.5 g/L), and immunoglobulin M 0.2 g/L (0.4 to 1.5 g/L). MRI brain performed 2 months from presentation showed improvement in globus pallidi and thalami bilaterally; otherwise there was no change, though the patient continued to be ataxic with impaired speech. Five months after presentation, the patient experienced worsening of gait, sensori-neural hearing loss (SNHL), and decreased truncal stability (EDSS 7.5). MRI showed progression of white matter abnormalities. Right frontal brain biopsy tested positive for enterovirus RNA by RT-PCR and viral particles were observed on electron microscopy. Treatment was commenced with IVIG 2 g/kg monthly and fluoxetine 4 mg daily, increasing to 20 mg daily. Sixteen months after presentation, the patient’s clinical status improved further (EDSS 1.0). Repeat CSF showed leukocyte count of 3 × 10(6)/L, erythrocyte count 0 × 10(6)/L, glucose 2.7 mmol/L, protein 0.23 g/L, and the patient tested negative for enterovirus by RT-PCR. MRI brain showed improvement, and the spinal cord MRI normalized. The authors stated that in this case, the combination of fluoxetine with IVIG may have had an additive effect, although these researchers were unable to conclude whether the IVIG, fluoxetine, or both ultimately contributed to the child's improved neurologic outcome. These researchers stated that this case served as a reminder of the need for a high index of suspicion for opportunistic infections, including chronic enterovirus infection, when rituximab is used. It also illustrated the potential benefit of fluoxetine and IVIG in the treatment of chronic enterovirus infections in children with acquired humoral immune deficiency.
Multisystem Inflammatory Syndrome in Children
McArdle and associates (2021) stated that evidence is urgently needed to support treatment decisions for children with multi-system inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. These investigators carried out an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. They used inverse-probability weighting and generalized linear models to evaluate IVIG as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were 2 primary outcomes: the 1st was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the 2nd was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation. Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the WHO criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio [OR] for the comparison with IVIG alone, 0.77; 95 % CI: 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted OR, 0.54; 95 % CI: 0.22 to 1.33). The adjusted ORs for a reduction in disease severity were similar in the 2 groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the 3 groups. The authors found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue.
Son and colleagues (2021) stated that the assessment of real-world effectiveness of immunomodulatory medications for MIS-C may guide therapy. These investigators analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the 1st day any such therapy for MIS-C was given) with IVIG plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. A total of 518 patients with MIS-C (median age of 8.7 years) received at least 1 immunomodulatory therapy; 75 % had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17 % versus 31 %; RR, 0.56; 95 % CI: 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8 % and 17 % of the patients, respectively (RR, 0.46; 95 % CI: 0.19 to 1.15), and shock resulting in vasopressor use in 13 % and 24 % (RR, 0.54; 95 % CI: 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34 % versus 70 %; RR, 0.49; 95 % CI: 0.36 to 0.65), but the risk of fever was unaffected (31 % and 40 %, respectively; RR, 0.78; 95 % CI: 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis. The authors concluded that among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone.
Ouldali and co-workers (2021) noted that MIS-C is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. In a retrospective, observational, cohort study, these researchers compared IVIG plus methylprednisolone versus IVIG alone as initial therapy in MIS-C. This trial was drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the WHO definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a 2nd-line therapy, hemodynamic support, acute left ventricular dysfunction after 1st-line therapy, and length of stay (LOS) in the pediatric intensive care unit (PICU). The primary analysis entailed propensity score matching with a minimum caliper of 0.1. Among 181 children with suspected MIS-C, 111 fulfilled the WHO definition (58 females [52 %]; median age of 8.6 years [inter-quartile range [IQR] of4.7 to 12.1]); 5 children did not receive either treatment. Overall, 3 of 34 children (9 %) in the IVIG and methylprednisolone group and 37 of 72 (51 %) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone versus IVIG alone was associated with lower risk of treatment failure (absolute RD, -0.28 [95 % CI: -0.48 to -0.08]; OR, 0.25 [95 % CI: 0.09 to 0.70]; p = 0.008). IVIG and methylprednisolone therapy versus IVIG alone was also significantly associated with lower risk of use of 2nd-line therapy (absolute RD, -0.22 [95 % CI: -0.40 to -0.04]; OR, 0.19 [95 % CI: 0.06 to 0.61]; p = 0.004), hemodynamic support (absolute RD, -0.17 [95 % CI: -0.34 to -0.004]; OR, 0.21 [95 % CI: 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute RD, -0.18 [95 % CI: -0.35 to -0.01]; OR, 0.20 [95 % CI: 0.06 to 0.66]), and duration of stay in the PICU (median of 4 versus 6 days; difference in days, -2.4 [95 % CI: -4.0 to -0.7]). The authors concluded that among children with MIS-C, treatment with IVIG and methylprednisolone versus IVIG alone was associated with a more favorable fever course. Study interpretation was limited by the observational design.
In a case-series study (n = 8), Kurz and Gombala (2021) stated that in view of the fact that MIS-C must be identified and treated early, these investigators started therapy regardless of the phenotype. All patients were treated with IVIG (usually for 2 to 3 days), high-dose cortisone, high-dose of aspirin, anti-thrombotic therapy with low-molecular heparin, and antibiotics. The treatment resulted in rapid clinical improvement. The patients' fever returned to normal, while inflammatory signs and elevated heart enzymes were reduced. Cardiac symptoms resolved and BP returned to normal in all patients; 3 patients had minor pericardial and pleural effusions at the time of discharge from the hospital. All 8 patients recovered and were discharged after 9 to 54 days of hospitalization (median of 13 days). None of the patients failed to respond, and none needed a 2nd cycle of immunoglobulins or biologic drugs. The authors noted that this treatment approach has also been confirmed recently in a retrospective study (Ouldali et al, 2021).
An UpToDate review on “COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome” (Son and Friedman, 2021) states that “For children with moderate or severe manifestations (e.g., shock requiring vasopressors, left ventricular [LV] systolic dysfunction, elevated troponin or brain natriuretic peptide, arrythmia, coronary artery [CA] aneurysm [Z-score ≥2.5], or other manifestations requiring pediatric intensive care unit [PICU] care), we suggest initial therapy with combined intravenous immune globulin (IVIG) plus a glucocorticoid rather than IVIG alone (Grade 2C). If IVIG is not available, treatment with glucocorticoids alone is acceptable. Observational studies suggest that initial combination therapy may hasten cardiac recovery and reduce the need for hemodynamic support and/or adjunctive immune-modifying therapy. The dosing for IVIG in this setting is 2 g/kg administered in a single infusion over 8 to 12 hours. Glucocorticoid therapy consists of intravenous methylprednisolone at a dose of 2 mg/kg/day in two divided doses. Once the patient has defervesced and is improved clinically, this can be transitioned to an equivalent oral dose of prednisolone or prednisone by the time of discharge and then tapered off over two to four weeks”.
On behalf of the Interest Group for Pediatric Neonatal Intensive Care (IGPNI) of the Swiss Society of Intensive Care and the Pediatric Infectious Diseases Group Switzerland, Schlapbach and colleagues (2021) noted that following the spread of the coronavirus disease 2019 (COVID-19) pandemic, a new disease entity emerged, defined as pediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS), or MIS-C. These researchers developed best practice recommendations for the diagnosis and treatment of children with PIMS-TS in Switzerland. They recommended, based on currently available reports and in line with other recommendations, to use IVIG in PIMS-TS patients presenting with shock, and to consider IVIG in PIMS-TS with undefined presentation. While IVIG should be usually administered as a single dose of 2 g/kg (maximum of 100 g/dose), clinicians should assess the cardiac and fluid status, especially in patients in shock, as in some patients a slower administration become necessary.
Appendix
Impaired Antibody Response to Pneumococcal Polysaccharide Vaccine
- Age 2 years and older: impaired antibody response demonstrated to vaccination with a pneumococcal polysaccharide vaccine
- Not established for children less than 2 years of age
- Excludes the therapy initiated in the hospital setting.
Examples of Risk Factors for Bleeding (not all inclusive)
- Undergoing a medical or dental procedure where blood loss is anticipated
- Comorbidity (eg, peptic ulcer disease, hypertension)
- Mandated anticoagulation therapy
- Profession or lifestyle predisposes patient to trauma (eg, construction worker, fireman, professional athlete).
The laboratory's own reference ranges should be used, where available. If the laboratory's reference ranges are not submitted with the immunoglobulin level results, the following standard reference ranges may be applied.
| Normal Immunoglobulin Levels (mg/dl) | Normal IgG Subclass Levels (mg/dl) | |||||||
|---|---|---|---|---|---|---|---|---|
| AGE | IgA | IgG | IgM | AGE | IgG1 | IgG2 | IgG3 | IgG4 |
| 1 - 2 mo | 1 - 53 | 251 - 906 | 20 - 87 | cord | 435 - 1084 | 143 - 453 | 27 - 146 | 1 - 47 |
| 2 - 3 mo | 3 - 47 | 206 - 601 | 17 - 105 | 0 - 3 mo | 218 - 496 | 40 - 167 | 4 - 23 | 1 - 33 |
| 3 - 4 mo | 4 - 73 | 176 - 581 | 24 - 101 | 3 - 6 mo | 143 - 394 | 23 - 147 | 4 - 100 | 1 - 14 |
| 4 - 5 mo | 8 - 84 | 172 - 814 | 33 - 108 | 6 - 9 mo | 190 - 388 | 37 - 60 | 12 - 62 | 1 - 1 |
| 5 - 6 mo | 8 - 68 | 215 - 704 | 35 - 102 | 9 mo - 3 yr | 286 - 680 | 30 - 327 | 13 - 82 | 1 - 65 |
| 6 - 8 mo | 11 - 90 | 217 - 904 | 34 - 125 | 3 - 5 yr | 381 - 884 | 70 - 443 | 17 - 90 | 1 - 116 |
| 8 mo - 1 yr | 16 - 84 | 294 - 1069 | 41 - 149 | 5 - 7 yr | 292 - 816 | 83 - 513 | 8 - 111 | 1 - 121 |
| 1 - 2 yr | 14 - 106 | 345 - 1213 | 43 - 173 | 7 - 9 yr | 442 - 802 | 113 - 480 | 15 - 133 | 1 - 84 |
| 2 - 3 yr | 14 - 123 | 424 - 1051 | 48 - 168 | 9 - 11 yr | 456 - 938 | 163 - 513 | 26 - 113 | 1 - 121 |
| 3 - 4 yr | 22 - 159 | 441 - 1135 | 47 - 200 | 11 - 13 yr | 456 - 952 | 147 - 493 | 12 - 179 | 1 - 168 |
| 4 - 6 yr | 25 - 154 | 463 - 1236 | 43 - 196 | 13 - 15 yr | 347 - 993 | 140 - 440 | 23 - 117 | 1 - 183 |
| 6 - 9 yr | 33 - 202 | 633 - 1280 | 48 - 207 | 15 yr & up | 422 - 1292 | 117 - 747 | 41 - 129 | 1 - 291 |
| 9 - 11 yr | 45 - 236 | 608 - 1572 | 52 - 242 | |||||
| 11 yr & up | 70 - 312 | 639 - 1349 | 56 - 352 | |||||
Aetna considers IVIG therapy experimental and investigational for any of the following conditions (in alphabetical order):
| Health Conditions | |
|---|---|
|
Acquired factor VIII inhibitors |
Malignancy, non-hematologic |
footnote1* The term "POEMS" is actually an acronym for the most common symptoms and signs of the syndrome: "P" - peripheral neuropathy (numbness, tingling, and weakness of the feet and hands); "O" - organomegaly (large organs, like the liver, lymph nodes and spleen); "E" - endocrinopathy (abnormal hormone levels including sex hormones, thyroid hormones, etc.); "M" - monoclonal plasma-proliferative disorder (a collection of abnormal bone marrow cells, called plasma cells); most patients will have at least on abnormal bone x-ray associated with these plasma cells; "S" - skin changes (increased skin pigment, increased body hair, thickening of the skin, etc).
| Brand of Immune Globulin | FDA-Approved Indications |
|---|---|
| Asceniv | Primary humoral immunodeficiency |
| Bivigam | Primary humoral immunodeficiency |
| Cutaquig (subcutaneous) | Primary immunodeficiencies |
| Cuvitru (subcutaneous) | Primary humoral immunodeficiency |
| Flebogamma | Primary immunodeficiencies |
| GamaSTANFootnote2** (intramuscular) | Hepatitis A, measles (rubeola), varicella, rubella |
| Gammagard | Primary immunodeficiencies |
| Gammaked | Primary immunodeficiencies, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy |
| Gammaplex | Primary immunodeficiencies |
| Gamunex-C | Primary immunodeficiencies, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy |
| Hizentra (subcutaneous) | Primary immunodeficiencies |
| HyQvia (subcutaneous) | Primary immunodeficiencies |
| Octagam | Primary immunodeficiencies |
| Panzyga | Primary humoral immunodeficiency, immune thrombocytopenic purpura |
| Privigen | Primary immunodeficiencies, immune thrombocytopenic purpura |
| Xembify (subcutaneous) | Primary humoral immunodefiencies |
Source: Prescribing Information.
Note: Primary immunodeficiencies includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.
Footnote2** An intra-muscular formulation of immune globulin, GamaSTAN S/D, has been approved for the following indications: prophylaxis of hepatitis A; prevention or modification of measles (rubeola) in persons exposed fewer than 6 days previously; passive immunization against varicella in immunosuppressed patients; prophylaxis of rubella in pregnancy when therapeutic abortion is not an option; and prevention of serious infection in patients with IgG deficiencies.
References
The above policy is based on the following references:
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- Abougergi MS, Kwon JH. Intravenous immunoglobulin for the treatment of Clostridium difficile infection: A review. Dig Dis Sci. 2011;56(1):19-26.
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