MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 1
Original Issue Date (Created): September 20, 2002
Most Recent Review Date (Revised): June 4, 2013
Effective Date: October 1, 2013
I. POLICY Intravenous Immune globulin (IVIg) Therapy
IVIg may be considered medically necessary for the following indications:
Primary immune deficiency syndromes, including combined immunodeficiencies.
X-linked agammaglobulinemia (Bruton’s)
X-linked hyper-IgM syndrome
Severe combined immunodeficiency (SCID)
Wiskott-Aldrich syndrome
Ataxia telangiectasia
Patients with primary immunodeficiency syndromes should meet all the following
criteria for treatment with immune globulin:
o Laboratory evidence of immunoglobulin deficiency (see Policy Guidelines)
o Documented inability to mount an adequate immunologic response to
inciting antigens (see Appendix)
o Persistent and severe infections despite treatment with prophylactic
antibiotics
Acute Humoral Rejection
Autoimmune Mucocutaneous Blistering Diseases in patients with severe, progressive
disease, despite treatment with conventional agents (corticosteroids, azathioprine,
cyclophosphamide, etc.)
pemphigus
pemphigoid
pemphigus vulgaris
pemphigus foliaceus
Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)
Autoimmune and inflammatory disorders
dermatomyositis refractory to treatment with corticosteroids; in combination with
other immunosuppressive agents
Kawasaki syndrome*;
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 2
Neuroimmunological
myasthenia gravis in patients with chronic debilitating disease in spite of treatment
with cholinesterase inhibitors, or complications from or failure of corticosteroids
and/or azathioprine.
myasthenic crisis (i.e., an acute episode of respiratory muscle weakness) in patients
with contraindications to plasma exchange
Guillain-Barre syndrome
chronic inflammatory demyelinating polyneuropathy*; in patients with progressive
symptoms for at least two months
multifocal motor neuropathy
Eaton-Lambert myasthenic syndrome; in patients who have failed to respond to
anticholinesterase medications and/or corticosteroids.
Hematologic
idiopathic thrombocytopenic purpura (ITP)
treatment of acute, severe ITP (see policy guidelines)
treatment of chronic ITP*; in patients with at least 6 months’ duration of disease,
and with persistent thrombocytopenia despite treatment with corticosteroids and
splenectomy
neonatal alloimmune thrombocytopenia;
allogeneic post-bone marrow transplant setting
B cell chronic lymphocytic leukemia (CLL); in patients with
hypogammaglobulinemia and persistent bacterial infections
warm antibody autoimmune hemolytic anemia, refractory to corticosteroids and
immunosuppressive agents
anti-phospholipid syndrome
severe anemia due to parvovirus B19
Infectious diseases
HIV [human immunodeficiency virus]-infected patients
toxic shock syndrome
patients with primary defective antibody synthesis
Transplantation
prior to solid organ transplant, treatment of patients at high risk of antibody-
mediated rejection, including highly sensitized patients, and those receiving an
ABO incompatible organ.
following solid-organ transplant, treatment of antibody-mediated rejection
* FDA-labeled indications
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 3
IVIg is considered not medically necessary as a treatment of relapsing/remitting multiple
sclerosis.
Other applications of IVIg therapy are considered investigational, including, but not limited to,
the following conditions:
chronic progressive multiple sclerosis;
refractory rheumatoid arthritis and other connective tissue diseases, including systemic
lupus erythematosus;
recurrent spontaneous abortion (see below for related laboratory tests);
inclusion-body myositis;
polymyositis, including refractory polymyositis;
myasthenia gravis in patients responsive to immunosuppressive treatment;
other vasculitides besides Kawasaki disease, including vasculitis associated with anti-
neutrophil cytoplasmic antibodies (ANCA; e.g., Wegener’s granulomatosis, polyarteritis
nodosa), Goodpasture’s syndrome, and vasculitis associated with other connective tissue
diseases;
thrombotic thrombocytopenic purpura;
hemolytic uremic syndrome;
paraneoplastic syndromes, other than Eaton-Lambert myasthenic syndrome
demyelinating polyneuropathy associated with IgM paraproteinemia;
epilepsy;
chronic sinusitis;
asthma;
chronic fatigue syndrome;
aplastic anemia;
Diamond-Blackfan anemia;
red cell aplasia;
acquired factor VIII inhibitors;
hemophagocytic syndrome;
acute lymphoblastic leukemia;
multiple myeloma;
immune-mediated neutropenia;
nonimmune thrombocytopenia;
cystic fibrosis;
recurrent otitis media;
diabetes mellitus;
Behcet’s syndrome;
adrenoleukodystrophy;
stiff person syndrome;
organ transplant rejection;
uveitis;
demyelinating optic neuritis;
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 4
recent-onset dilated cardiomyopathy;
Fisher syndrome
pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections
(PANDAS);
autism
complex regional pain syndrome
Alzheimer’s disease
IGG sub-class deficiency
neonatal sepsis
Crohn’s disease
opsoclonus-myoclonus;
birdshot retinopathy;
epidermolysis bullosa acquisita;
necrotizing fasciitis;
polyradiculoneuropathy (other than CIDP).
Subcutaneous Immune Globulin (SCIg) Therapy
SCIg may be considered medically necessary for the treatment of primary
immunodeficiencies*, including congenital agammaglobulinemia, hypogammaglobulinemia,
common variable immunodeficiency (CVID), severe combined immunodeficiency, Wiskott-
Aldrich syndrome, and X-linked agammaglobulinemia (XLA).
Policy Guidelines
Primary Immunodeficiency Syndromes. The diagnosis of immunodeficiency and post
immunization titers must be taken in context with the clinical presentation of the patient and
may vary dependent on the type of vaccine given and the prior immunization history of the
patient. The following parameters are examples of criteria for diagnosis of the primary
immunodeficiency syndromes.
Laboratory evidence of immunoglobulin deficiency may include the following
definitions:
Agammaglobulinemia (total IgG less than 200 mg/dL)
Persistent hypogammaglobulinemia (total IgG less than 400 mg/dL, or at least
two standard deviations below normal, on at least two occasions)
Absence of B lymphocytes
Inability to mount an adequate antibody response to inciting antigens may include the
following definitions:
Lack of appropriate rise in antibody titer following provocation with a
polysaccharide antigen. For example, an adequate response to the pneumococcal
vaccine may be defined as at least a four-fold increase in titers for at least 50%
of serotypes tested.
Lack of appropriate rise in antibody titer following provocation with a protein
antigen. For example, an adequate response to tetanus/diphtheria vaccine may
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 5
be defined as less than a four-fold rise in titers 3-4 weeks after vaccine
administration.
According to a 2010 national guideline from Canada on immune globulin for primary immune
deficiency, although higher trough levels of IVIg may be associated with clinical response; the
goal of IVIg dose increases should be to improve clinical effectiveness and not merely to
increase trough levels.
Acute, severe ITP may be defined by the following parameters:
acute ITP with major bleeding, e.g., life-threatening bleeding and/or clinically important
mucocutaneous bleeding
acute ITP with severe thrombocytopenia and at high risk for bleeding complications
acute ITP with severe thrombocytopenia and a slow or inadequate response to
corticosteroids
acute ITP with severe thrombocytopenia and a predictable risk of bleeding in the future,
e.g., a procedure or surgery with a high bleeding risk.
Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) should meet the
diagnostic criteria established by the American Academy of Neurology, particularly if the patient
also is diagnosed with chronic fatigue syndrome. (See Appendix A for the diagnostic criteria.) In
addition, by intravenous immunoglobulin infusion (IVIg), treatment should be limited to CIDP
patients who do not respond to initial therapy with prednisone and are experiencing serious
clinical worsening. In patients treated for chronic diseases, such as CIDP, multifocal motor
neuropathy, and dermatomyositis, the effect of IVIg is transitory and therefore periodic infusions
of IVIg are needed to maintain treatment effect. The frequency of transfusions is titrated to the
treatment response; typically, biweekly or monthly infusions are needed.
Patients with multifocal motor neuropathy should meet established diagnostic criteria such as
those published by Van Asseldonk and colleagues in Lancet Neurology in 2005 (See Appendix B
for the diagnostic criteria).
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 6
The following is an adaptation of recommendations that have been made for IVIg dosing in a
consensus report from the IVIg advisory committee:
Disorder Dose
Primary immunodeficiency disorders 0.4-0.6 g/kg every 28 days
Chronic inflammatory demyelinating polyneuropathy (CIDP) 0.4 g/kg for 5 doses
Guillain-Barré syndrome 0.25-0.4 g/kg × 5 doses
Dermatomyositis 0.4 g/kg for 5 doses
Idiopathic thrombocytopenia 0.4 g/kg/d × 5 days
Acute humoral rejection 1 g/kg/d for 2 doses
Cross-reference:
MP-7.006 Pregnancy-Related Testing for Genetic, Chromosomal, Metabolic, and
Immunologic Abnormalities
MP-2.304 Pervasive Developmental Disorders
MP-4.031 Plasma Exchange
MP-2.068 Extracorporeal Photophoresis after Solid-Organ Translplant and for Graft-Versus
Host Disease, and Cutaneous T-Cell Lymphoma
II. PRODUCT VARIATIONS [N] = No product variation, policy applies as stated
[Y] = Standard product coverage varies from application of this policy, see below
[N] Capital Cares 4 Kids [N] Indemnity
[N] PPO [N] SpecialCare
[N] HMO [N] POS
[Y] SeniorBlue HMO* [Y] FEP PPO**
[Y] SeniorBlue PPO*
* For treatment of Autoimmune Mucotaneous Blistering Diseases, refer to Centers for Medicare and
Medicaid (CMS) National Coverage Determination (NCD) 250.3 Intravenous Immune Globulin
for the Treatment of Autoimmune Mucocutaneous Blistering Diseases. For IVIG given in the home
for treatment of primary immunodeficiency, refer to NHIC LCD 27260 Intravenous Immune Globulin
and Local Coverage Article for Intravenous Immune Globulin effective January 2011 (A46761). For the
treatment of second-line therapy in acute relapse of relapsing multiple sclerosis (MS), refer to Novitas
Solutions Local Coverage Determination LCD L32937 - Intravenous Immune Globulin (IVIG).
Also, for off-label uses of drugs and biologicals, refer to the following Medicare Benefit Policy Manual
sections: “FDA approved drugs used for indications other than what is indicated on the official label may
be covered under Medicare if determined that the use is medically accepted, taking into consideration the
major drug compendia, authoritative medical literature and/or accepted standards of medical practice.”
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 7
Refer to Medicare Benefit Policy Manual (100-2, Chapter 15, Section 50.4.2- Unlabeled Use of Drug).”
http://www.cms.gov/manuals/Downloads/bp102c15.pdf
Off-label use of FDA approved drugs and biologicals used in an anti-cancer chemotherapeutic regimen
for medically accepted indications may be covered under Medicare if the indications are supported in
either one or more Medicare recognized compendia or in peer-reviewed literature. Refer to Medicare
Benefit Policy Manual (100-2, Chapter 15, Section 50.4.5- Off-Label Use of Drugs and Biologicals in an
Anti-Cancer Chemotherapeutic Regimen) for the compendia list.
http://www.cms.gov/manuals/Downloads/bp102c15.pdf
**Refer to the FEP Medical Policy Manual MP-10.04.03 IVIG / IGSC Immune Globulin. The
FEP Medical Policy manual can be found at:
http://bluewebportal.bcbs.com/landingpagelevel3/504100?docId=23980
III. DESCRIPTION/BACKGROUND This policy addresses the use of human immune globulin therapy for preventing and/or treating
a wide variety of disorders in the outpatient setting. Both intravenous infusion (IVIg) and
subcutaneous infusion (SCIg) of immune globulin are addressed. However, the policy only
considers nonspecific pooled preparations of IVIg, not other preparations used for passive
immunization to specific antigens.
Human immune globulin therapy provides a broad spectrum of opsonizing and neutralizing
immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral antigens. Three
formulations of human IgG are available for delivery by intravenous infusion (IVIg), by
subcutaneous infusion (SCIg), or by intramuscular (IMIg) depot injections. IMIg has been
largely abandoned in the United States because volume constraints and pain preclude delivery
of sufficient product weekly into each buttock to yield therapeutic serum levels of IgG, leaving
recipients susceptible to infections. Thus, this policy focuses on IVIg and SCIg for conditions
that typically would be treated in an outpatient setting.
Intravenous infusion immune globulin is an antibody-containing solution obtained from the
pooled plasma of healthy blood donors that contains antibodies to greater than 10 million
antigens. IVIg has been used to correct immune deficiencies in patients with either inherited or
acquired immunodeficiencies and has also been investigated as an immunomodulator in
diseases thought to have an autoimmune basis. Several IVIg products are available for clinical
use in the United States. The labeled indications approved by the U.S. Food and Drug
Administration (FDA) for IVIg are listed in the Policy section. A variety of off-label indications
have been investigated; some of the most common are inflammatory myopathies, neuropathies
(e.g., Guillain-Barre syndrome), myasthenia gravis, multiple sclerosis, and solid organ
transplantation.
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 8
This policy only addresses nonspecific pooled preparations of IVIg; it does not address other
immunoglobulin preparations that are specifically used for passive immunization to prevent or
attenuate infection with specific viral diseases such as respiratory syncytial virus,
cytomegalovirus, or hepatitis B.
Subcutaneous infusion immune globulin is used for treating patients with primary
immunodeficiencies (PID). A genetic basis for more than 80 different types of PID has been
discovered, the most common being primary antibody deficiency (PAD) that is associated with
low levels or total lack of normal circulating immunoglobulins. The first FDA-approved SCIg
product, Vivaglobin, is a pasteurized, polyvalent human normal immune globulin product that is
manufactured from large pools of human plasma by cold alcohol fractionation with no chemical
or enzymatic alterations. Vivaglobin administration produces relatively stable steady-state serum
levels of IgG that are representative of those seen in a normal human population.
Applications of this product for conditions other than primary immunodeficiencies are
considered off-label in the United States and are not addressed in this policy. In recent years,
other SCIg products have also received FDA-marketing approval.
Regulatory Status Several IVIg have been approved by the FDA. These include Carimune (ZLB Bioplasma),
Flebogamma (Grifols), Gammagard (Baxter), Gamunex (Talecris Biotherapeutics), Octagam
(Octapharma), Polygam S/D (Baxter) Privigen (CSL Behring LLC).
Several SCIg products have received FDA marketing approval for primary immunodeficiencies.
These include Vivaglobin® (ZLB Behring LLC, Kankakee, IL), Hizentra® (ZLB Behring LLC,
Kankakee, IL), Gamunex-C® (Talecris Biotherapeutics, Inc., Research Triangle Park, NC), and
Gammaked® (Kedrion Biopharma, Cambridge, MA).
IV. DEFINITIONS ANTIBODY is a protein substance produced in response to a unique antigen. The substance
developed combines with a specific antigen to destroy or control it.
IMMUNE GLOBULIN is a drug created from serum containing antibodies. It is used to supply
necessary antibodies to patients with immunoglobulin deficiencies and to provide passive
immunity against common viral infections (e.g., hepatitis A and measles).
INTRAVENOUS refers to within or into a vein.
OFF LABEL refers to the use of a drug to treat a condition for which it has not been approved by
the U.S. Food and Drug Administration (FDA), especially when such may relieve unpleasant
symptoms or prove compassionate. Drug effects that have been observed but not specifically
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 9
proven (and for which no application has been made) may be exploited for unproven or "off-
label" uses by licensed medical practitioners.
V. BENEFIT VARIATIONS The existence of this medical policy does not mean that this service is a covered benefit under
the member's contract. Benefit determinations should be based in all cases on the applicable
contract language. Medical policies do not constitute a description of benefits. A member’s
individual or group customer benefits govern which services are covered, which are excluded,
and which are subject to benefit limits and which require preauthorization. Members and
providers should consult the member’s benefit information or contact Capital for benefit
information.
VI. DISCLAIMER Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute medical
advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of
members. Members should discuss any medical policy related to their coverage or condition with their provider
and consult their benefit information to determine if the service is covered. If there is a discrepancy between this
medical policy and a member’s benefit information, the benefit information will govern. Capital considers the
information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law.
VII. REFERENCES A phase III study evaluating safety and effectiveness of immune globulin intravenous (IGIV
10%) for the treatment of mild to moderate Alzheimer’s disease. Sponsored by Baxter
Healthcare Corporation. Last updated March 30, 2010. Available online at
ClinicalTrials.gov. Last accessed February 27, 2013.
Berger M, Murphy E, Riley P et al. Improved quality of life, immunoglobulin G levels and
infection rates in patients with primary immunodeficiency diseases during self-treatment with
subcutaneous immunoglobulin G. South Med J 2010; 103(9):856-63.
Bucuvalas JC, Anand R. Treatment with immunoglobulin improves outcome for pediatric liver
transplant recipients. Liver Transpl 2009 15(11):1564-9.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.
Publication 100-02. Chapter 15. Sections 50, 50.4.1, 50.4.3. Drugs and Biologicals. Effective
10/01/03. [Website]: . http://www.cms.gov/Regulations-and-
Guidance/Guidance/Manuals/downloads/bp102c15.pdf Accessed February 27, 2013..
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.
Publication 100-02. Chapter 15. Section 50.4.5. Off-Label Use of Anti-Cancer Drugs and
Biologicals. [Website]: http://www.cms.gov/Regulations-and-
Guidance/Guidance/Manuals/downloads/bp102c15.pdf Accessed February 27, 2013.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.
Publication 100-02. Chapter 15. Section 50.4.2. Unlabeled Use of Drug. Effective 10/01/03.
[Website]: http://www.cms.gov/Regulations-and-
Guidance/Guidance/Manuals/downloads/bp102c15.pdf Accessed February 27, 2013.
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 10
Centers for Medicare and Medicaid Services (CMS) National Coverage Determination (NCD)
250.3 Intravenous Immune Globulin for the Treatment of Autoimmune Mucotaneous
Blistering Diseases. Effective 10/01/02. CMS [Website]: https://www.cms.gov Accessed
February 27, 2013.
Centers for Medicare and Medicaid Services (CMS) Intravenous Immune Globulin Local
Coverage Article for Intravenous Immune Globulin - Policy Article - Effective January 2011
(A46761) Effective 01/01/1. [Website]: http://www.cms.gov/medicare-coverage-
database/details/article-
details.aspx?articleId=46761&ver=10&ContrId=137&ContrVer=1&LCDId=27260&Cntrc
trSelected=137*1&Cntrctr=137&name=NHIC%2c%2bCorp.%2b(16003%2c%2bDME%2b
MAC)&LCntrctr=137*1&kq=1829415601&ua=highwire&IsPopup=y& Accessed
February 27, 2013.Chuhjo T, Nakao S, Matsuda T. Successful treatment of persistent
erythroid aplasia caused by parvovirus B19 infection in a patient with common variable
immunodeficiency with low-dose immunoglobulin. Am J Hematol 1999; 60(3):222-4.
Crabol Y, Terrier B, Rozenberg F et al. Intravenous Immunoglobulin Therapy for Pure Red
Cell Aplasia Related to Human Parvovirus B19 Infection: A Retrospective Study of 10
Patients and Review of the Literature. Clin Infect Dis 2013 [Epub ahead of print].
Durable Medical Equipment Regional Carrier (DMERC) Region A Local Coverage
Determination (LCD) L5044. External Infusion Pumps. Effective 2/4/2011. [Website]:
http://www.medicarenhic.com/dme/medical_review/mr_lcds/mr_lcd_current/L5044_2011-
07-22_rev_2013-02_PA_2013-01.pdf Accessed February 27, 2013.
Durable Medical Equipment Regional Carrier (DMERC) Region A Local Coverage
Determination (LCD) 27260 Intravenous Immune Globulin Effective 01/01/12. [Website]:
http://www.cms.gov/medicare-coverage-database/details/article-
details.aspx?articleId=46761&ver=10&ContrId=137&ContrVer=1&LCDId=27260&Cntrc
trSelected=137*1&Cntrctr=137&name=NHIC%2c%2bCorp.%2b(16003%2c%2bDME%2b
MAC)&LCntrctr=137*1&kq=1829415601&ua=highwire&IsPopup=y& Accessed
February 27, 2013.
Franco AC, Torrico AC, Moreira FT et al. Adjuvant use of intravenous immunoglobulin in the
treatment of neonatal sepsis: a systematic review with a meta-analysis. J Pediatr (Rio J)
2012; 88(5):377-83.
Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane
Database Syst Rev 2012; 12:CD002277.
Goebel A, Baranowski A, Maurer K et al. Intravenous immunoglobulin treatment of the
complex regional pain syndrome. Ann Intern Med 2010; 152(3):152-8.
Goebel A, Baranowski A, Maurer K et al. Intravenous immunoglobulin treatment of the
complex regional pain syndrome. Ann Intern Med 2010; 152(3):152-8.
Gurcan HM, Jeph S, Ahmed AR. Intravenous immunoglobulin therapy in autoimmune
mucocutaneous blistering diseases: a review of the evidence for its efficacy and safety. Am J
Clin Dermatol 2010; 11(5):315-26.
Hematological malignancies and hematopoietic stem cell transplantation. Cochrane Database
Syst Rev 2008; (4):CD006501.
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
Page 11
Hoffmann F, Grimbacher B, Thiel J et al. Home-based subcutaneous immunoglobulin G
replacement under real-life conditions in children and adults with antibody deficiency. Eur J
Med Res 2010; 15(6):238-45.
Huang YC, Li YC, Chen TJ. The efficacy of intravenous immunoglobulin for the treatment of
toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol 2012;
167(2):424-32.
Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barre
syndrome. Cochrane Database Syst Rev 2012; 7:CD002063.
Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barre
syndrome. Cochrane Database Syst Rev 2010; (6):CD002063.
INIS Collaborative Group. Treatment of neonatal sepsis with intravenous immune globulin. N
Engl J Med 2011; 365(13):1201-11.
Ito S, Oyake T, Uchiyama T et al. Successful treatment with cyclosporine and high-dose gamma
immunoglobulin for persistent parvovirus B19 infection in a patient with refractory
autoimmune hemolytic anemia. Int J Hematol 2004; 80(3):250-3.
Koduri PR, Kumapley R, Khokha ND et al. Red cell aplasia caused by parvovirus B19 in AIDS:
use of i.v. immunoglobulin. Ann Hematol 1997; 75(1-2):67-8.
Miyasaka N, Hara M, Koike T et al. Effects of intravenous immunoglobulin therapy in Japanese
patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized
double-blind placebo-controlled trial. Mod Rheumatol 2012; 22(3):382-93.
Moore ML, Quinn JM. Subcutaneous immunoglobulin replacement therapy for primary
antibody deficiency: advancements into the 21st century. Ann Allergy Asthma Immunol 2008;
101(2):114-21. Nobile-Orazio E, Cocito D, Jann S et al. Intravenous immunoglobulin versus
intravenous methylprednisolone for chronic inflammatory demyelinating
polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 2012; 11(6):493-502.
Novitas Solutions. Local Coverage Determination (LCD) L32937. Intravenous Immune
Globulin. Effective 04/04/13. [Website]: https://www.novitas-solutions.com/policy/mac-
ab/l32937.html Accessed February 27, 2013.
Patwa HS, Chaudhry V, Katzberg H et al. Evidence-based guideline: intravenous
immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and
Technology Assessment Subcommittee of the American Academy of Neurology. Neurology
2012; 78(13):1009-15.
Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane
Database Syst Rev 2006; (2):CD000112.
Raanani P, Gafter-Gvili A, Paul M et al. Immunoglobulin prophylaxis in hematological
malignancies and hematopoietic stem cell transplantation. Cochrane Database Syst Rev
2008; (4):CD006501.
Relkin NR, Szabo P, Adamiak B et al. 18-month study of intravenous immunoglobulin for
treatment of mild Alzheimer disease. Neurobiol Aging 2009; 30(11):1728-36.
Rogosnitzky M, Danks R, Holt D. Intravenous immunoglobulin for the treatment of Crohn's
disease. Autoimmun Rev 2012 [Epub ahead of print].
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
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Shehata N, Palda V, Bowen T et al. The use of immunoglobulin therapy for patients with
primary immune deficiency: an evidence-based practice guideline. Transfus Med Rev 2010;
24(Suppl 1):S28-50.
Shehata N, Palda VA, Meyer RM et al. The use of immunoglobulin therapy for patients
undergoing solid organ transplantation: an evidence-based practice guideline. Transfus Med
Rev 2010; 24(Suppl 1):S7-27.
Silvergleid AJ, Berger M. General principles in the use of immune globulin. In UpToDate
Online Journal [serial online]. Waltham, MA: UpToDate. Updated December 14,
2012..[Website]: www.uptodate.com. Accessed February 27, 2013.
Taber’s Cyclopedic Medical Dictionary, 19th edition.
Wang DX, Shu XM, Tian XL et al. Intravenous immunoglobulin therapy in adult patients with
polymyositis/dermatomyositis: a systematic literature review. Clin Rheumatol 2012;
31(5):801-6.
VIII. CODING INFORMATION Note: This list of codes may not be all-inclusive, and codes are subject to change at any time.
The identification of a code in this section does not denote coverage as coverage is
determined by the terms of member benefit information. In addition, not all covered
services are eligible for separate reimbursement.
Covered when medically necessary:
CPT Codes® 90283 90284 96365 96366 96369 96370 96371
Current Procedural Terminology (CPT) copyrighted by American Medical Association. All Rights Reserved.
HCPCS
Code Description
J1459 Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1556 Injection, immune globulin (bivigam), 500 mg
J1557 Injection, immune globulin (Gammaplex), intravenous, non-lyophilized (e.g., liquid), 500 mg
J1559 Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg
J1561 Injection, immune globulin (Gamunex/Gamunex-C/Gammaked), non-lyophilized (e.g., liquid), 500 mg
J1562 Injection, immune globulin (Vivaglobin), 100 mg
J1566 Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg
J1568 Injection, immune globulin (Octagam) intravenous, non-lyophilized (e.g., liquid), 500 mg
J1569 Injection, immune globulin (Gammagard) intravenous, non-lyophilized (e.g., liquid), 500 mg
J1572 Injection, immune globulin (Flebogamma/Flebogamma DIF), intravenous, non-lyophilized (e.g.,
liquid), 500 mg
J1599 Injection, immune globulin, intravenous, non-lyophilized (e.g., liquid), not otherwise specified, 500
mg
MEDICAL POLICY
POLICY TITLE IMMUNE GLOBULIN
POLICY NUMBER MP-2.023
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ICD-9-CM
Diagnosis
Code*
Description
040.82 Streptococcus infection in conditions classified elsewhere and of unspecified site
041.00 – 041.9 Bacterial infection, code range
042.0 Human immunodeficiency virus (HIV) disease
204.10 Chronic lymphoid leukemia, without mention of having achieved remission
204.11 Chronic lymphoid leukemia in remission
279.00 Unspecified hypogammaglobulinemia
279.2 Combined immunity deficiency
279.3 Other selective immunoglobulin deficiencies
279.04 Congenital hypogammaglobulinemia
279.05 Immunodeficiency with increased igm
279.06 Common variable immunodeficiency
279.12 Wiskott-aldrich syndrome
279.2 Combined immunity deficiency
279.3 Unspecified immunity deficiency
287.3 – 287.39 Primary thrombocytopenia
287.4 – 287.49 Secondary thrombocytopenia
287.5 Unspecified thrombocytopenia
289.81 Primary hypercoagulable state
334.8 Spinocerebellar disease
354.0 -355.9 Mononeuritis, code range
356.4 356.9 Idiopathic peripheral neuropathy, code range
357.0 Acute infective polyneuritis
357.81 Chronic inflammatory demyelinating polyneuritis
358.01 Myasthenia gravis with (acute) exacerbation
358.1 Myasthenic syndromes in diseases classified elsewhere
4260-4269 Conduction disorders, code range
695.14 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome
694.4 – 694.5 Pemphigus/pemphigoid code range
446.1 Acute febrile mucocutaneous lymph node syndrome (Kawasaki disease)
710.3 Dermatomyositis
757.39 Other specified congenital anomaly of skin
776.1 Transient neonatal thrombocytopenia
V42.81 Status post-bone marrow transplant
*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.
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The following ICD-10 diagnosis codes will be effective October 1, 2014:
ICD-10-CM
Diagnosis
Code*
Description
A48.3 Toxic shock syndrome
B95.0-B95.8 Streptococcus, staphylococcus and enterococcus as the cause of diseases classified elsewhere
code range
B20 Human immunodeficiency virus [HIV] disease
C91.10-C91.12 Chronic lymphocytic leukemia of b-cell type code range
D59.1 Other autoimmune hemolytic anemias (includes warm type)
D68.61 Anticardiolipin syndrome (includes antiphospholipid syndrome)
D80.0-D80.9 Immunodeficiency with predominantly antibody defects code range
D83.0-D83.9 Common variable immunodeficiency code range
G35 Multiple sclerosis
G60.0 –G60.9 Hereditary and idiopathic neuropathy
G61.0 Guillain-Barre syndrome
G70.01 Myasthenia gravis with (acute) exacerbation
G73.3 Myasthenic syndromes in other diseases classified elsewhere
I 44.0 – I45.9 Other conduction disorders
L10.0 – L10.9 Pemphigus code range
L12.0 – L12.9 Pemphigoid code range
L51.3 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome
M30.0 Mucocutaneous lymph node syndrome
M33.90 – M33.99 Dermatopolymyositis unspecified
P61.0 Transient neonatal thrombocytopenia
Z94.81 Bone marrow transplant status
*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.
IX. POLICY HISTORY MP 2.023 CAC 5/27/03
CAC 1/25/05
CAC 1/31/06
CAC 9/26/06
CAC 9/25/07
CAC 7/29/08
7/1/09 Administrative Change Cross-reference added for Pervasive Developmental
Disorders
CAC 9/29/09 Gamunex added to list of IVIG preparations in
background/description. References updated.
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CAC 9/28/10 Consensus review.
CAC 10/25/11 Consensus review
CAC 4/24/12 Adopt BCBSA.The following were added as medically necessary:
Primary immune deficiency syndromes, including combined immunodeficiencies
X-linked hyper-IgM syndrome
Ataxia telangiectasia
Autoimmune Mucocutaneous Blistering Diseases, in patients with severe,
progressive disease despite treatment with conventional agents (corticosteroids,
azathioprine, cyclophosphamide, etc.)
Pemphigus
pemphigoid*
pemphigus vulgaris
pemphigus foliaceus
Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)
Neuroimmunological
Eaton-Lambert myasthenic syndrome; in patients who have failed to respond
to anticholinesterase medications and/or corticosteroids
Infectious diseases
toxic shock syndrome
IVIg is considered not medically necessary as a treatment of relapsing/remitting
multiple sclerosis. Previously this indication was listed as investigational.
The following indications were added as investigational:
Fisher syndrome
pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infections (PANDAS);
autism
complex regional pain syndrome
Alzheimer’s disease
IgG sub-class deficiency
Sepsis
FEP variation updated.
CAC 6/4/13 Minor revision. “Neonatal”added to bullet point on sepsis in the
investigational statement. Crohn’s disease, opsoclonus-myoclonus, birdshot
retinopathy;, epidermolysis bullosa acquisita , necrotizing fasciitis and
polyradiculoneuropathy (other than CIDP) were all added as examples of
investigational indications. Severe anemia associated with parvovirus B19
was added as a medically necessary indication under hematologic indications.
12/19/2013- New 2014 Code updates made. Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company®,
Capital Advantage Assurance Company® and Keystone Health Plan® Central. Independent licensees of the BlueCross BlueShield Association.
Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies.
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X. APPENDIX
Appendix A:
Diagnostic Criteria for Diagnosis of Chronic Inflammatory Demyelinating
Polyneuropathy (CIDP) The following criteria are adapted from the Task Force Report of the Ad Hoc Subcommittee
of the American Academy of Neurology AIDS Task Force. (Neurology 1991; 41(5):617-8)
The report included mandatory, supportive, and exclusionary diagnostic criteria. Only the
mandatory criteria are excerpted here. The criteria are based on a combination of clinical
observations, physiologic studies, pathologic features (i.e., nerve biopsy), and studies of the
cerebrospinal fluid (CSF).
I. Clinical
Mandatory 1.Progressive or relapsing motor and sensory, rarely only motor or sensory, dysfunction of
more than 1 limb or a peripheral nerve nature, developing over at least 2 months.
2.Hypo- or areflexia. This will usually involve all 4 limbs.
II. Physiologic Studies
Mandatory Nerve conduction studies including studies of proximal nerve segments in which the
predominant process is demyelination.
Must have 3 of 4:
1. Reduction in conduction velocity (CV) in 2 or more motor nerves:
a. <80% of lower limit of normal (LLN) is amplitude >80% of LLN
b.<70% of LLN is amplitude <80% of LLN
2. Partial conduction block or abnormal temporal dispersion in 1 or more motor nerves:
either peroneal nerve between ankle and below fibular head, median nerve between wrist
and elbow, or ulnar nerve between wrist and below elbow.
Criteria suggestive of partial conduction block: <15% change in duration between proximal
and distal sites and >20% drop in negative peak (p) area or peak to peak (p-p) amplitude
between proximal and distal sites.
Criteria for abnormal temporal dispersion and possible conduction block: >15% change in
duration between proximal and distal sites and >20% drop in p area or p-p amplitude
between proximal and distal sites and >20% drop in p or p-p amplitude between proximal
and distal sites.
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These criteria are only suggestive of partial conduction block as they are derived from
studies of normal individuals. Additional studies, such as stimulation across short segments
or recording of individual motor unit potentials, are required for confirmation.
3. Prolonged distal latencies in 2 or more nerves:
a. >125% of upper limit of normal (LEN) is amplitude >80% of LLN
b.>150% of LEN if amplitude <80% of LLN.
4. Absent F waves or prolonged minimum
a. >120% of ULN if amplitude >80% of LLN
b.>150% of ULN if amplitude <80% of LLN.
III. Pathologic Features
Mandatory Nerve biopsy showing unequivocal evidence of demyelination and remyelination.
Demyelination by either electron microscopy (>5 fibers) or teased fiber studies >12% of 50
fibers, minimum of 4 internodes each, demonstrating demyelination/remyelination.
IV. CSF Studies
Mandatory 1. Cell count <10 per cubic mm if HIV-seronegative or <50 per cubic mm is HIV
seropositive
2. Negative VDRL
The following criteria are adapted from the Joint Task Force of the EFNS and the PNS.
European Federation of Neurological Societies/Peripheral Nerve Society Guideline on
management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint
task force of the European Federation of Neurological Societies and the Peripheral Nerve
Society. J Peripher Nerv Syst. 2005;10:220-228. The EFNS/PNS diagnostic criteria were
designed to balance specificity and sensitivity.
V. Inclusion Criteria
1. Typical CIDP – Chronically progressive, stepwise, or recurrent symmetric proximal
and distal weakness and sensory dysfunction of all extremities, developing over at least
2 months; cranial nerves may be affected; and absent or reduced tendon reflexes in all
extremities
2. Atypical CIDP
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One of the following, but otherwise as in typical CIDP (tendon reflexes may be normal in
unaffected limbs):
Predominantly distal weakness (distal acquired demyelinating symmetric, DADS)
Pure motor or sensory presentations, including chronic sensory immune
polyradiculoneuropathy affecting the central process of the primary sensory neuron
Asymmetric presentations (multifocal acquired demyelinating sensory and motor,
MADSAM, Lewis-Sumner syndrome
Focal presentations (e.g., involvement of the brachial plexus or of one or more
peripheral nerves in one upper limb
Central nervous system involvement (may occur with otherwise typical or other forms
of atypical CIDP)
VI. Exclusion Criteria Diphtheria, drug or toxin exposure likely to have caused the neuropathy
Hereditary demyelinating neuropathy, known or likely because of family history, foot
deformity, mutilation of hands or feet, retinitis pigmentosa, ichthyosis, liability to
pressure palsy
Presence of sphincter disturbance
Multifocal motor neuropathy
Antibodies to myelin-associated glycoprotein
VII. Electrodiagnostic Criteria
1. Definite
At least one of the following:
At least 50% prolongation of motor distal latency above the upper limit of normal
values in two nerves, or
At least 30% reduction of motor conduction velocity below the lower limit of normal
values in two nerves, or
At least 20% prolongation of F-wave latency above the upper limit of normal values in
two nerves (>50% if amplitude of distal negative peak CMAP, 80% of lower limit of
normal values), or
Absence of F-waves in two nerves if these nerves have amplitudes of distal negative
peak CMAPs at least 20% of lower limit of normal values + at least one other
demyelinating parameter* in at least one other nerve, or
Partial motor conduction block: at least 50% amplitude reduction of the proximal
negative peak CMAP relative to distal, if distal negative peak CMAP at least 20% of
lower limit of normal values, in two nerves, or in one nerve + at least one other
demyelinating parameter* in at least one other nerve, or
Abnormal temporal dispersion (>30% duration increase between the proximal and
distal negative peak CMAP) in at least two nerves, or
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Distal CMAP duration (interval between onset of the first negative peak and return to
baseline of the last negative peak) of at least 9 ms in at least one nerve + at least one
other demyelinating parameter* in at least one other nerve
2. Probable At least 30% amplitude reduction of the proximal negative peak CMAP relative to
distal, excluding posterior tibial nerve, if distal negative peak CMAP at least 20% of
lower limit of normal values, in two nerves, or in one nerve + at least one other
demyelinating parameter* in at least one other nerve
3. Possible As in (1) but in only one nerve
CMAP, compound muscle action potential. To apply these criteria, the median, ulnar
(stimulated below the elbow), peroneal (stimulated below the fibular head), and tibial
nerves on one side are tested. Temperatures should be maintained at least 33° C at the
palm and 30° C at the external malleolus (good practice points).
* Any nerve meeting any of the criteria
VIII. Supportive Criteria
Elevated cerebrospinal fluid protein with leukocyte <10/mm3 (level A recommendation)
Magnetic resonance imaging showing gadonlinium enhancement and /or hypertrophy of
the cauda equine, lumbosacral or cervical nerve roots, or the brachial or lumbosacral
plexus (level C recommendation)
Nerve biopsy showing unequivocal evidence of demyelination and/or remyelination in >5
fibers by electron microscopy or in >6 of 50 teased fibers
Clinical improvement following immunomodulatory treatment (level A recommendation)
Appendix B:
Diagnostic Criteria for Diagnosis of Multifocal Motor Neuropathy (MMN) The following are proposed diagnostic criteria adapted from a 2005 article by Van Asseldonk
and colleagues (Lancet Neurology; 4: 309-319)
I. Clinical criteria 1. Slow or stepwise progressive limb weakness
2. Asymmetrical limb weakness
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3. Fewer than seven affected limb regions (on each side: upper arm, lower arm, upper leg,
or lower leg)
4. Tendon reflexes in affected limbs are decreased or absent
5. Signs and symptoms more pronounced in arms than in legs
6. 20–65 years old at disease onset
7. No objective sensory abnormalities except for vibration sense
8. No bulbar signs or symptoms
9. No upper-motor-neuron features
10. No other neuropathies
11. No myopathy (e.g., dystrophy, inclusion-body myositis)
II. Laboratory criteria 1. CSF protein less than 1 g/L
2. High anti-GM1 titre
3. High signal intensity on T2-weighted MRI of the brachial plexus
III. Electrodiagnostic criteria 1. Definite motor conduction block: Compound muscle action potential (CMAP) area
reduction on proximal versus distal stimulation of at least 50% over a long segment
(between erb and axilla, upper arm, lower arm, lower leg), or a CMAP amplitude
reduction on proximal versus distal stimulation of at least 30% over a short distance (2·5
cm) detected by inching. CMAP amplitude on stimulation of the distal part of the
segment with motor conduction block of at least 1 mV
2. Probable motor conduction block: CMAP amplitude reduction on proximal versus distal
stimulation of at least 30% over a long segment of an arm nerve. CMAP amplitude on
stimulation of the distal part of the segment with motor conduction block of at least 1 mV
3. Slowing of conduction compatible with demyelination: Motor conduction velocity
(MCV) <75% of the lower limit of normal; DML or shortest F wave latency 130% of the
upper limit of normal or absence of F waves all after 16–20 stimuli. CMAP amplitude on
distal stimulation of at least 0·5 mV
4. Normal sensory-nerve conduction in arm segments with motor conduction block. Normal
sensory nerve action potential (SNAP) amplitudes on distal stimulation.
Definite MMN: 1–11 on clinical criteria, 1 on laboratory criteria, and 1 and 4 on
electrodiagnostic criteria
Probable MMN: 1–3 and 6–11 on clinical criteria, 1 on laboratory criteria, and 2 and 4 on
electrodiagnostic criteria
Possible MMN: 1 and 7–11 on clinical criteria, 2 or 3 on laboratory criteria, and 3 and 4 on
electrodiagnostic criteria
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