Intravenous Immune Globulin (IVIG) is a solution of human immunoglobulin specifically prepared for intravenous infusion. Immunoglobulin contains a broad range of antibodies that specifically act against bacterial and viral antigens.
The use of intravenous immune globulin should be reserved for patients with serious defects of antibody function. The goal is to provide immunoglobulin G (IgG) antibodies to those who lack them.IVIG infusion may have other effects beyond simple antibiody replacement. Coverage will be provided for intravenous immune globulin when it is used in treatment of the following conditions:
1.Primary Humoral Immunodeficiency Syndromes
IVIG is indicated for the treatment of patients with primary immunodeficiency syndromes such as common variable immunodeficiency (CVID), congenital agammaglobulinemia (X-linked agammaglobulinemia), severe combined immunodeficiency (SCID), X-linked immunodeficiency with hyperimmunoglobulin M (IgM), and Wiskott-Aldrich syndrome to replace or boost immunoglobulin G (IgG).
Common variable immunodeficiency (CVID), also known as acquired hypogammaglobulinemia, adult-onset hypogammaglobulinemia, and dysgammaglobulinemia, is characterized by reduced serum immunoglobulins, impaired antibody responses, and heterogenous clinical features. It is a rare syndrome, affecting one in 50,000 to one in 200,000 people. In most patients, the onset is in the second or third decade of life. The most common clinical presentation of CVID is an increased susceptibility to infection. Because patients with CVID are predisposed to chronic lung disease and pulmonary deterioration as a result of chronic or subclinical infection, early recognition of the diagnosis and initiation of the IVIG therapy are critical. Patients with CVID can also develop a variety of autoimmune and inflammatory disorders and are also at risk for inflammatory bowel disease.
Once the diagnosis of CVID is suspected based on clinical presentation, laboratory confirmation should be made. A low serum IgG level is the most consistent laboratory abnormality in CVID, with most patients having concurrent deficiencies of IgA and IgM. However, there are rare instances when a patient will have normal IgG levels. Therefore, the serum immunoglobulin measurement alone does not establish a diagnosis of CVID. A definitive diagnosis of CVID is established when a patient does not demonstrate an antibody response or rejection to immunization with protein antigens (e.g., tetanus) or carbohydrate antigens (e.g., pneumococcal capsular polysaccharides such as Pneumovax).
The following diagnostic evidence is required to support a diagnosis of CVID:
- Laboratory reports demonstrating an IgG level of less than 400 mg/dl for the assay utilized, and lack of response to immunization (see below);
- An IgG level greater than or equal to 400mg/dl with evidence of recurrent severe infections with documented antibiotic therapy and lack of response to immunization (see below);
- Laboratory reports demonstrating a lack of ability to produce an antibody response to a protein antigen (e.g., tetanus) or one of the polysaccharide antigens (e.g., Pneumococcal polysaccharide or H. Influenza type B). Two or more immunizations should have been given in the 12 months prior to laboratory assessment of antibody response. The exception maybe when a severe adverse reaction has occurred with the last immunization and two have been given over 12 month or longer interval. Pneumococcal titers are measured differently among different laboratories with some measuring 4, 5, 6, 12, or 14 serotypes. An adequate response of the serotypes tested should include a two to three fold increase in titers in at least 50 percent of the serotypes.
Reimbursement will not be provided for the initiation or continuation of intravenous immune globulin therapy based solely on a low IgG value, there must be a demonstrated lack of ability to produce an adequate antibody response to protein or carbohydrate antigens. There is no scientific rationale for IVIG therapy and it will be considered not medically reasonable and necessary, when used in patients with normal humoral immunity but with recurrent infections. The use of IVIG for recurrent viral upper respiratory infection will not be considered medically reasonable and necessary. Sinopulmonary disease which merits the use of IVIG is defined as a documented pneumonia, bronchiectasis, chronic bronchitis, recurrent bacterial or mycoplasma bronchitis, pneumonitis and documented episodes of acute bacterial sinusitis requiring extensive and/or recurrent courses of antibiotics. The goal of using IVIG therapy in this situation to prevent progressive lung disease and avoid other serious bacterial infections including meningitis, sepsis, solid organ abscess, osteomylitis, or other bacterial infection of sufficient severity to merit hospitalization
When IVIG is indicated in immunodeficient individuals (as defined above), with recurrent or chronic bacterial sinusitis, the medical record must document findings diagnostic of, or highly suggestive of, recurrent or chronic bacterial sinus infection. Such findings may include, but are not limited to, fever, unilateral purulent nasal discharge and unilateral facial pain." Absence of these findings will not preclude the use of IVIG, however, documentation will be considered insufficient to justify medical necessity when antibiotic therapy is prescribed routinely during the first few days of symptoms in the absence of these findings, or in the instance where antibiotic therapy is prescribed by phone without the benefit of an examination by a physician (or qualified non-physician practitioner). The fact that antibiotic therapy is prescribed for an episode of sinusitis will not be considered, in and of itself, evidence of bacterial sinus infection. IVIG is never indicated and therefore not reasonable and necessary for the treatment of simple viral rhinosinusitis, even in immunodeficient individuals and even if recurrent. Recurrent rhinosinustis is defined as the occurrence of four or more episodes of acute rhinosinustis per year with interim symptom resolution. Chronic sinusitis is defined as an episode of rhinosinustis that persists for greater than 12 weeks.
Patients who have been receiving long term IVIG therapy for Primary Humoral Immunodeficiency Syndromes may have undergone diagnostic testing in the remote past, the results of which may no longer be available. Repeat testing for the purpose of re-confirming the diagnosis is not necessary. Similarly, repeat testing with new technology, not available at the time or original testing for the purpose of diagnostic confirmation is also not necessary. The medical record must document that the patient has been receiving long term IVIG therapy .
The dosing regimen for patients with CVID is not standardized, but is based primarily on the clinical response. Generally, checking trough levels of IgG and functional antibody levels are not medically necessary more frequently than every 3-6 months. A patient will generally receive initial IVIG doses of 400-600 mg/kg every 3-4 weeks titrating the dose and interval to achieve serum trough levels of at least 400 mg/dl or 300 mg/dl above the baseline IgG level. Documentation should support the rationale for a serum trough level greater than 300 mg above the baseline IgG. IVIG replacement in these patients is usually life-long.
Maintenance doses exceeding the 400-600 mg/kg range may be covered, but only if the desired clinical response to 400-600 mg/kg is clearly documented as inadequate as evidenced by serum trough levels below 400mg/dl.
- Congenital agammaglobulinemia (X-linked agammaglobulinemia) is an inherited deficiency that appears in the first 3 years of life and occurs in one out of 10,000 people. Quantitative immunoglobulins show marked deficits or absence of all five immunoglobulin classes. Peripheral blood B-lymphocytes are usually absent.
- Severe combined immunodeficiency (SCID) is a rare and fatal inherited syndrome that has an incidence of approximately one in 1,000,000 people. The typical case involves an infant less than one year of age. The lymphocyte counts are significantly below normal, the levels of B- and T-lymphocytes are absent or below normal, the lymphocyte response to mitogen is absent or below normal, and the quantitative measurements of IgG, IgA, and IgM show marked deficits.
- X-linked immunodeficiency with hyperimmunoglobulin M (IgM) is similar to X-linked agammaglobulinemia, however, these patients sometimes have lymphoid hyperplasia. The concentrations of serum IgG, IgA, and IgE are very low, whereas the serum IgM concentration is either normal or, more frequently, greatly elevated and polyclonal.
- Wiskott-Aldrich syndrome is an X-linked recessive syndrome characterized by eczema, thrombocytopenia purpura with normal-appearing megakaryocytes but small defective platelets, and undue susceptibility to infection. Patients usually present during infancy. Survival beyond the teens is rare.
For congenital agammaglobulinemia (X-linked agammaglobulinemia), severe combined immunodeficiency (SCID), X-linked immunodeficiency with hyperimmunoglobulin M (IgM), and Wiskott-Aldrich syndrome, the dosage variability is based on a patient’s condition and disease type, providers must adhere to the current clinical standard of practice and recommended dosage in current literature. Any time there is a departure from the standard dosing, the rationale for this must be documented in the medical record.
- A patient will generally receive initial IVIG doses of 400-600 mg/kg every 3-4 weeks titrating the dose and interval to achieve serum trough levels of at least 500 mg/dl or 300 mg/dl above the baseline IgG level. IVIG replacement in these patients is usually life-long.
- Maintenance doses exceeding the 400-600 mg/kg range may be covered, but only if the desired clinical response to 400-600 mg/kg is clearly documented as inadequate as evidenced by serum trough levels below 400mg/dl.
2. IVIG in Children with Human Immunodeficiency Virus (HIV) Disease who do not have ITP
IVIG may be medically necessary to reduce significant bacterial infections when all three primary criteria and one of the secondary criteria are met:
1.Age less than 13 years
2.IgG level less than 400 mg/dl
3.Entry CD4+ lymphocyte cell count is greater than or equal to 200/mm3
1.Two or more bacterial infections in a 1-year period despite antibiotic chemoprophylaxis with TMP-SMZ or another active agent
2.The child has received two doses of measles vaccine and lives in a region with a high prevalence of measles
3.The child has chronic bronchiectasis whose immunological response is suboptimal to antimicrobial and pulmonary therapy
4.The child has immune abnormalities with symptomatic or asymptomatic HIV, as evidenced by a lack of ability to produce an antibody response to immunization with protein antigens (e.g., tetanus) or carbohydrate antigens (e.g., pneumococcal capsular polysaccharides. such as, Pneumovax).
Dosage guideline: For pediatric (HIV) Infection is 400-mg/kg body weight given every 28 days to prevent serious bacterial infection. Claims reimbursed with dosages in larger or decreased frequency of administration are subject to medical review, like any service.
5. Neurological Disorders
IVIG is indicated for the treatment of patients with neurological disorders such as Guillain-Barre’ syndrome, relapsing-remitting multiple sclerosis, chronic inflammatory demyelinating polyneuropathy (and variant syndromes such as Multifocal Motor Neuropathy), myasthenia gravis, refractory polymyositis, and refractory dermatomyositis. However, it is noted that not all patients with these diagnoses require treatment with IVIG.
IVIG therapy will only be considered medically reasonable and necessary for these neurological disorders when there is evidence of rapid progression of the disease or relapse or when other forms of treatment have failed or are contraindicated. The physician must document the rationale for the choice of therapy and consider disease activity, concurrent illness, venous access, side effects and drug availability in the decision of which therapy to prescribe and in what sequence.
For each of these diseases, the diagnosis of the disorder must be unequivocal. There must be clinical (history, quantitative examination), electrophysiological motor-sensory nerve conductions, electromyography (EMG), cerebrospinal fluid (CSF), and when necessary, biopsy (muscle-nerve) data to support the diagnosis. This must be clearly documented in the medical record and conclusions based upon this information must be consistent with accepted standards of care, in order for IVIG treatment to be considered reasonable and necessary.
Once IVIG treatment is initiated, meticulous documentation of progress is required. If there is initial improvement, and continued treatment is necessary, quantitative assessment to monitor the progress is required (e.g., ADL measurements). Changes in these parameters must be clearly documented. Subjective or experiential improvement alone is insufficient to either continue IVIG or to expect coverage.
There must be evidence of an attempt to wean the dosage when improvement has occurred. This “weaning” may be either a reduction in the frequency of administration and/or a reduction in dosage. There must be an attempt to stop the IVIG infusion if improvement is sustained with dosage reduction. If improvement does not occur with IVIG, then IVIG therapy is not indicated and should be discontinued. Generally, objective clinical improvement should occur within three months of the start of the IVIG therapy. If objective clinical improvement does not occur within this time frame, further administration of IVIG will be considered not medically reasonable and necessary.
Maintenance dosing for neurologic disorders should be individualized such that the minimum dose required to maintain clinical response is used for those patients who require chronic therapy. Where it is necessary to administer larger doses than noted in the dosage guidelines, the medical record must document that such higher doses are required to maintain response. Such documentation must include evidence that lower doses are not efficacious in producing the needed functional response for any individual patient.
- Guillain-Barre’ syndrome is an acute, frequently severe, and fulminant inflammatory demyelinating polyneuropathy that occurs at a rate of approximately one case in a million per month. An infection generally precedes the onset of neuropathy by 1 to 3 weeks. A small proportion occurs within 1 to 4 weeks of a surgical procedure. The clinical features include ascending paralysis, hyporeflexia or areflexia, parasthesias, and elevated spinal fluid protein levels. Pain, particularly in the back and extremities may be reported in up to two thirds of cases. Electrophysiologic evidence includes prolonged or absent F waves and absent H reflexes. Increased distal latencies, conduction blocks with temporal depression of motor responses also occur followed by slowing of nerve conduction velocities. Intravenous administration of high-dose immunoglobulin given over 5 days has been proven effective.
Dosage Guidelines: 1,000 mg/kg body weight daily for two days; or 400 mg/kg body weight daily for five days.
- Multiple Sclerosis that is relapsing-remitting is characterized by unpredictable recurrent attacks of neurological dysfunction. Attacks generally evolve over days to weeks and may be followed by complete, partial, or no recovery. Patients with a relapsing-remitting course experience no progression of neurological impairment between attacks. The age of onset is generally between 15 and 60 years. IVIG has not as yet been shown to be clinical benefit in patients with progressive forms of multiple sclerosis. IVIG will be covered for the treatment of multiple sclerosis only when there is clear documentation of relapsing remitting disease.
Dosage Guidelines: Usual dosing is 200-400 mg/kg every 4 weeks.
- Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) includes a group of chronic progressive or relapsing, inflammatory demyelinating peripheral neuropathies that are manifested by physiological abnormalities such as partial conduction block,slowed nerve conduction velocities manifested by prolonged distal motor latencies and/or delayed or absent F waves, or dispersion of compound muscle action potentials. Clinical features include chronic progressive or relapsing symmetric weakness with sensory loss and high spinal fluid protein levels. In addition, IVIG may be approved for CIDP patients, who had no response or an inadequate response to corticosteroids, who have experienced unacceptable side effects to the use of corticosteroids and dosage reduction is not clinically feasible or have contraindications to steroids. The physician will be required to substantiate the contraindication(s) in the medical record.
Dosage Guidelines for:
- Initial therapy - 400 mg/kg body weight per day for five days
- Maintenance therapy - 250-400 mg/kg body weight no more frequently than every two weeks.
6. Myasthenia gravis is a disorder of neuromuscular transmission characterized by fluctuating weakness and fatigability. It is attributed to blockage of the acetylcholine receptor at the neuromuscular end-plates by anti-acetylcholine receptor autoantibodies. The diagnosis of myasthenia gravis is confirmed by a positive Tensilon test. Anticholinesterase drugs or thymectomy are generally the first treatments for this condition
IVIG is indicated in those patients with myasthenia gravis who have failed to respond to, or have intolerable side effects to acetylcholinesterase inhibitors, are either refractory to corticosteroids over a 6 week period; have been unable to successfully taper corticosteroids below moderately high doses; or develop severe side effects due to steroid therapy; and have also failed at least one immunosuppressive agent (e.g., azathiprime, Methotrexate, cyclophosphamide, cyclosporine). Thymectomy must be considered in patients who have evidence of thymoma prior to the use of IVIG. IVIG will be considered medically reasonable and necessary as a first line therapy for Myasthenic crisis or preoperatively for planned thymectomy. Length of treatment with IVIG will vary due to the remittent and recurrent nature of this condition.
Dosage Guidelines: At this time, there is no clearly established dozing regimen, although many studies have reported success with a dose of 400 mg/kg weight per day for five days.
7. Polymyositis and dermatomyositis are conditions in which the skeletal muscle is damaged by a nonsuppurative inflammatory process dominated by lymphocytic infiltration. Polymyositis begins acutely or insidiously with muscle weakness, tenderness, and discomfort. Proximal muscles more often than distal muscles are affective. Dermatomyositis involves characteristic skin changes that may precede or follow the muscle syndrome and include a localized or diffuse erythema, maculopapular eruption, scaling eczematoid dermatitis, or rarely, an exfoliative dermatitis. The classic lilac-colored (heliotrope) usually manifested on the eyelids, bridge of the nose, cheeks (butterfly distribution), forehead, chest, elbows, knees and knuckles, and around the nailbeds. Periorbital edema is frequent.
Diagnostic studies to support a diagnosis of polymyositis or dermatomyositis include an elevated creatine phosphokivase (CPK), an abnormal electromyography (EMG), and/or an abnormal muscle biopsy. The differential diagnosis of polymyositis and dermatomyositis includes other entities which may cause muscle weakness including drug induced myopathy, necrotizing myopathy, hypothyroidism, HIV infection, myasthenia gravis, inherited metabolic myopathies and the muscular dystrophies. Diagnostic studies, along with the history and physical examination must clearly document the diagnosis to be polymyositis or dermtomyositis.
IVIG is indicated in those patients with polymyositis or dermatomyositis who are either refractory to corticosteroids over a 6 week period administered as Prednisone 1 mg/kg or equivalent; have been unable to successfully taper corticosteroids below moderately high doses even with the addition of other immunosupressive agents; or develop severe side effects due to steroid therapy; and have also failed at least one immunosuppressive agent (e.g., azathioprime, Methotrexate, cyclophosphamide, cyclosperine). Patients who fail to show a response to initial therapies are considered to have resistant disease. Resistant disease is defined by a lack of normalization of the serum creatine kinase (CK) by 4-6 weeks and/or a failure to regain muscle strength in three months. Before treatment with IVIG, consideration should be given to alternative diagnoses. Length of treatment with IVIG will vary due to the remittent and recurrent nature of these conditions. The need for continuation of IVIG must be documented and would be demonstrated by continued decreased muscle strength, elevated CPKs, and/or EMG abnormalities.
Dosage Guidelines: 1,000 mg/kg body weight daily for two days every four weeks or 400mg/kg body weight for five days every four weeks in patients intolerant of high-dose therapy.
Note: For patients who are unable to tolerate corticosteroid or immunosuppressive agents, or in the rare instance that these agents are contraindicated for the patient, treatment for polymyositis or dermatomyositis will be covered only if medical record documentation clearly indicates the reason that the patient cannot take the corticosteroid or immunosuppressive agent
a. Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia is a disorder of accumulation of mature-appearing lymphocytes in blood marrow and other organs. The symptoms usually develop gradually and include fatigue, shortness of breath with activity, weight loss, or frequent infections of the skin, lungs, kidneys, or other sites. Recurrent infections are a frequent complication.
IVIG is indicated for the prevention of recurrent bacterial infections and an immunoglobulin G (IgG) level of less then 600 mg/dl in patients with hypogammaglobulinemia associated with B-cell chronic lymphocytic leukemia (CLL) in order to help correct the patient’s immunity deficiency.
Dosage guideline for this disease process is 400 mg/kg body weight given every 3 – 4 weeks.
b. Hematopoetic Stem Cell Transplantation (HSCT)
IVIG is indicated to prevent the risk of acute graft-versus-host disease, associated interstitial pneumonia (infectious or idiopathic) and infections (e.g., cytomegalovirus infections [CMV], varicella-zoster virus infection, and recurrent bacterial infection) after HSCT in patients 20 years of age or older during the first 100 days after transplantation. It is not indicated in HSCT patients younger than 20 years of age, nor is it recommended for autologous transplants.
Dosage guideline is 500 mg/kg body weight given on days –7 and –2 pre-transplantation, then weekly through day 90 post-transplantation.
c .Kawasaki Disease (mucocutaneous Lymph Node Syndrome)
Kawasaki disease is an acute childhood vasculitis, the diagnosis of which is made based on clinical criteria. These criteria include fever of at least five (5) days duration and at least four (4) of the following: (1) polymorphic exanthem, (2) changes in the oropharynx such as fissured lips and strawberry tongue without discrete lesions, (3) changes in the extremities such as edema of the hands and feet and erythema of the palms and soles, (4) bilateral conjunctival infection without exudate, and (5) cervical lymphadenopathy, often singular and unilateral. IVIG is indicated for the treatment of Kawasaki disease when used in conjunction with aspirin.
Dosage guideline: 400 mg/kg body weight for four (4) consecutive days or a single infusion of 2,000 mg/kg body weight.
d. Autoimmune Hemolytic Anemia
Autoimmune hemolytic anemia is an acquired anemia induced by the binding of autoantibodies and/or a complement to the red cells. Signs and symptoms may include, but are not limited to, weakness, fatigue, exertional dyspnea, pallor, jaundice, tachycardia, splenomegaly, hepatomegaly, and anemia. In the majority of patients, this disease can be controlled by steroid therapy alone, by splenectomy or by a combination of these.
In this condition, intravenous immune globulin is indicated only for those patients who have failed to respond to other forms of therapy and/or require rapid cessation of hemolysis due to severe or life threatening manifestations of this condition. Other therapies showing treatment efficacy include corticosteroids, immunosuppressive and cytotoxic agents and monoclonal antibodies such as Rituximab. Duration of treatment is generally a short course of 3-5 weeks. Realizing dosage may vary based on patient’s individual situation; dosage must be in keeping with the recommended current literature and standard of practice.
Dosage guidelines: Realizing dosage may vary based on a patient’s individual situation, the dosage must be in keeping with the recommended dosage in current literature and the standard of practice. Any time there is a departure from the standard dosing, the rationale for this must be documented in the medical record.
e. Autoimmune Neutropenia
Autoimmune neutropenia is a hematologic disorder in which there is a decreased number of neutrophilic leukocytes in the blood due to an autoimmune mechanism. The disease is usually benign and self-limiting, and treatment beyond antibiotics is not frequently required. Occasionally, however, it is marked by repeated infection. IVIG may be recommended for the treatment of an absolute neutrophil count less than 800mm with recurrent bacterial infections.
Dosage guidelines are 1 to 2 g/kg of IVIG over 1 to 2 days.
f. Autoimmune Mucocutaneous Blistering Diseases
Effective October 1, 2002, IVIG is covered for the treatment of biopsy-proven (1) Pemphigus Vulgaris, (2) Pemphigus Foliaceus, (3) Bullous Pemphigoid, (4) Mucous Membrane Pemphigoid (a.k.a., Cicatricial Pemphigoid), and (5) Epidermolysis Bullosa Acquista for the following patient subpopulations:
1. Patients who have failed conventional therapy such as corticosteroids (prednisone at not less than 1 mg/kg or equivalent), azathioprine or mycophenolate mofetil;
2. Patients in whom conventional therapy is otherwise contraindicated; or
3. Patients with rapidly progressive disease in whom a clinical response could not be affected quickly enough using conventional agents. In such situations IVIG therapy would be given along with conventional treatment(s) and the IVIG would be used only until the conventional therapy could take effect.
Dosage guidelines: 2,000 mg/kg body weight per month divided into 1 to 5 doses.
In addition, IVIG for the treatment for autoimmune mucocutaneous blistering diseases must be used only for short-term therapy and not as a maintenance therapy.
g. Multiple Myeloma
IVIG is indicated in patients with multiple myeloma to reduce the incidence of recurrent bacterial infection when the patient is in the plateau phase of the disease and there is evidence of immunodeficiency as indicated by a serum IgG level <600mg/dl and a history of one documented, serious bacterial infection requiring IV antibiotic therapy in the previous six months or two or more such infections in the previous one year. IVIG will also be considered medically necessary when there has been a failure to mount an appropriate IgG humoral response to pneumococcal vaccine. IVIG therapy is not considered medically reasonable and necessary during primary induction chemotherapy or during a relapse of the disease
IVIG is considered medically reasonable and necessary for the following off-label indications:
- Stiff-man syndrome. Please refer to the utilization guidelines and documentation requirements for specific criteria related to coverage.
- Hypogammaglobulinemia with NNI (non neutropenic infection) induced by certain agents (All criteria must be met):
1. Recent treatment with rituximab in combination with cytotoxic chemotherapy
2. Laboratory proven hypogammaglobulinemia and an absolute neutrophil count over 1,000.
3. Acute infection requiring hospitalization or an infection lasting over 2 weeks in spite of antibiotics or an infection relapsing immediately after discontinuation of antibiotics.
4. Dose: 400-600 mg/kg one time that can be repeated at a standard interval based on laboratory assessment of IG levels and persistence of non neutropenic infection.
h. Chronic Graft versus Host Disease (GVHD)
IVIG is indicated in patient with chronic GVHD who meet all of the following criteria
Laboratory proven hypogammaglobulinemia with IgG levels <400 mg/dl.
At least one acute infection requiring hospitalization and/or parenteral antibiotics
Confirmed diagnosis of chronic GVHD
At least 100 days post transplant.