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Posted: April 2011

National Medical Policy

Subject: Policy Number: IVIG for Primary Immunodeficiencies NMP99

Effective Date*: January 2004 Updated: April 2006, April 2008, April 2011

This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source

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Reference/Website Link

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Immune Globulin Intravenous (IVIG): http://www.cms.gov/medicare-coveragedatabase/search/advanced-search.aspx Intravenous Immune Globulin (IVIG): http://www.cms.gov/medicare-coveragedatabase/search/advanced-search.aspx

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Current Policy Statement (Update April 2011 ­ A Medline search failed to reveal

any studies that would cause Health Net, Inc. to change its current position) Health Net, Inc. considers intravenous immunoglobulin (IVIG) medically necessary for treatment of patients with primary immunodeficiencies * when all of the following are met: 1. Hypogammaglobulinemia (significant reduction in total IgG [< 400 mg/dL] or IgG subclasses (see tables below **) Note: Common variable immunodeficiency (CVID), the most frequently diagnosed primary immunodeficiency, is characterized by a low serum IgG level antibody deficiency at least 2 SDs below the mean for age, 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 to immunization with protein antigens (e.g., tetanus) or carbohydrate antigens (e.g., pneumococcal capsular polysaccharides such as pneumovax). Therefore, we require the following diagnostic evidence to support a diagnosis of CVID: Laboratory reports demonstrating a normal to low IgG level for the assay utilized; and Laboratory reports demonstrating a lack of ability to produce an antibody response to protein or carbohydrate antigens (e.g., tetanus, pneumococcal capsular polysaccharides such as pneumovax). 2. Patient has documented either 1 very serious, laboratory-proven bacterial infection within preceding 6 months or 2 or more bacterial infections in preceding 1 year requiring IV antibiotic infusion therapy in the home or in the hospital. Note: We will not consider the initiation or continuation of IVIG therapy medically necessary for patients with mild sinopulmonary disease. Note: For patients with normal humoral immunity but recurrent infections, particularly upper respiratory infections, we will not consider IVIG medically necessary because it has no scientific basis. Note: The use of IVIG may not be beneficial in secondary immunodeficiency states correction of the underlying condition is the preferred approach. Dosage Guidelines: (see Adjustment of IVIG Dose below): Adult: 400 mg/kg body weight given every 3 - 4 weeks (with a range of 100 to 600 mg/kg IV every month) Pediatric: 400 - 600 mg/kg every month Lifelong Treatment Serum trough IgG level should measured before the infusion, then monitor every 3 months to maintain low normal level (usually 400 - 600mg/dl)

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Posted: April 2011 References for Dosage Guidelines: 1. Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. 2001 Aug 7;135(3):165-74. 2. Stiehm ER. Human intravenous immunoglobulin in primary and secondary antibody deficiencies. Pediatr Infect Dis J. 1997 Jul;16(7):696-707.

* Primary immunodeficiencies include:

· · · · · · Selective IgA Immunodeficiency Selective IgM Immunodeficiency Selective IgG subclass deficiency Congenital hypogammaglobulinemia Immunodeficiency with near/normal IgM (absent IgG, IgA) ­ a.k.a. Hyper IgM syndrome Severe combined immunodeficiency disorders (e.g., X-SCID, jak3, ZAP70, ADA, PNP, RAG defects, Ataxia Telangiectasia, Wiskott-Aldrich syndrome, DiGeorge syndrome, Common Variable Immunodeficiency)

Normal Immunoglobulin Levels (mg/dl)

AGE 1 - 2 mo 2 - 3 mo 3 - 4 mo 4 - 5 mo 5 - 6 mo 6 - 8 mo 8 mo - 1 yr 1 - 2 yr 2 - 3 yr 3 - 4 yr 4 - 6 yr 6 - 9 yr 9 - 11 yr 11 yr & up IgA 1 - 53 3 - 47 4 - 73 8 - 84 8 - 68 11 - 90 16 - 84 14 - 106 14 - 123 22 - 159 25 - 154 33 - 202 45 - 236 70 - 312 IgG 251 - 906 206 - 601 176 - 581 172 - 814 215 - 704 217 - 904 294 - 1069 345 - 1213 424 - 1051 441 - 1135 463 - 1236 633 - 1280 608 - 1572 639 ­ 1349 IgM 20 - 87 17 - 105 24 - 101 33 - 108 35 - 102 34 - 125 41 - 149 43 - 173 48 - 168 47 - 200 43 - 196 48 - 207 52 - 242 56 - 352

Normal IgG Subclass Levels (mg/dl)

AGE IgG1 IgG2 IgG3 IgG4

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cord 0 - 3 mo 3 - 6 mo 6 - 9 mo 9 mo ­ 3 3 - 5 yr 5 - 7 yr 7 - 9 yr 9 - 11 yr 11 - 13 yr 13 - 15 yr 15 yr & up yr

435 - 1084 218 - 496 143 - 394 190 - 388 286 - 680 381 - 884 292 - 816 442 - 802 456 - 938 456 - 952 347 - 993 422 - 1292

143 - 453 40 - 167 23 - 147 37 - 60 30 - 327 70 - 443 83 - 513 113 - 480 163 - 513 147 - 493 140 - 440 117 - 747

27 - 146 4 - 23 4 - 100 12 - 62 13 - 82 17 - 90 8 - 111 15 - 133 26 - 113 12 - 179 23 - 117 41 - 129

1 - 47 1 - 33 1 - 14 1-1 1 - 65 1 - 116 1 - 121 1 - 84 1 - 121 1 - 168 1 - 183 1 - 291

Adjustment of IVIG Dose

The use of intravenous immune globulin should be reserved for patients with serious defects of antibody function. The goal is to provide immune globulin to those who lack it. All immune deficiency conditions require ongoing monitoring of the patient's clinical condition with measurement of preinfusion (trough) serum IgG levels. Each patient's IVIG dosage should be optimized to the lowest dosage necessary to provide consistent control of their symptoms with the lowest risk of complications. Adjustment of the IVIG dose and time interval between doses should be based on trough levels measured every month for the first three months of therapy. After the first 3 months, if therapy is effective, the serum trough IgG level should be measured again at six months (or sooner if clinically indicated). For persons who have a high catabolism of infused IgG, more frequent infusions (e.g., every 2 ­ 3 weeks) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required. To reduce infection frequency in immunodeficient patients, serum trough levels should be maintained at 670 ­ 730 mg/dl, a value close to the lower limit of normal. All IgG trough levels outside of the low normal range of 6.7 ­ 7.3 mg/dl require dosage adjustment according to the sliding scale below:

IVIG Dose Sliding Scale for Patients with Hypogammaglobulinemia

Trough Level (mg/dl) 400 ­ 420 430 ­ 450 460 ­ 480 490 ­ 510 520 ­ 560 570 ­ 600 610 ­ 660 Multiplication Factor 1.7 1.6 1.5 1.4 1.3 1.2 1.1

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670 ­ 730 740 ­ 820 830 ­ 930 940 ­ 1070 1080 ­ 1270 1280 ­ 1550 1560 ­ 2000 For example: Current dose = 300 mg/kg Dose calculation:

1.0 0.9 0.8 0.7 0.6 0.5 0.4

IgG Trough Level = 1080 mg/dl

(Current Dose ______mg) x (Multiplication Factor ______ ) = New Dose _______mg Therefore: 300 mg x 0.6 = 180 mg for next dose

Codes Related To This Policy ICD-9 Codes

279.00 Hypogammaglobulinemia, unspecified · Agammaglobulinemia 279.01 Selective IgA immunodeficiency 279.02 Selective IgM immunodeficiency 279.03 Other selective immunoglobulin deficiencies · Selective deficiency of IgG 279.04 Congenital hypogammaglobulinemia · Agammaglobulinemia: · Bruton's type · X-linked 279.05 Immunodeficiency with increased IgM · Immunodeficiency with hyper-IgM: · autosomal recessive · X-linked 279.06 Common variable immunodeficiency · Dysgammaglobulinemia (acquired) (congenital) (primary) · Hypogammaglobulinemia: · acquired primary · congenital non-sex-linked · sporadic 279.09 Deficiency of humoral immunity; other (Transient hypogammaglobulinemia of infancy) 279.11 DiGeorge's syndrome · Pharyngeal pouch syndrome · Thymic hypoplasia 279.12 Wiskott-Aldrich syndrome 279.2 Combined immunity deficiency

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90283 Immune globulin (IgIV), human, for intravenous use 90765 Intravenous infusion for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour (deleted 12/2010) 90766 Intravenous infusion for therapy, prophylaxis, or diagnosis (specify substance or drug); (list separately in addition to code for primary procedure) (deleted 12/2010) 90780 Intravenous infusion for therapy/diagnosis, administered by physician or under direct supervision of physician; up to one hour (deleted 12/31/2005) 90781 each additional hour, up to eight hours (deleted 12/31/2005) 96365 Intravenous infusion for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour 96366 Intravenous infusion for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour

CPT Codes

HCPCS Codes

C9270 Injection, immune globulin, (Gammaplex), intravenous, nonlyophilized (e.g., liquid), 500 mg J1561 Injection, immune globulin, (Gamunex), intravenous, nonlyophilized (e.g.,liquid), 500 mg J1563 Injection, immune globulin, intravenous, 1gm (deleted 12/31/2005) J1564 Injection, immune globulin, 10 mg (deleted 12/31/2005) J1566 Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg J1567 Injection, immune globulin, intravenous, non-lyophilized (e.g., liquid) 500 mg (deleted 12/31/07) J1568 Injection, immune globulin, (Octagam), intravenous, nonlyophilized e.g.,liquid), 500 mg J1569 Injection, immune globulin, (Gammagard liquid), intravenous, non lyophilized, (e.g.,liquid), 500 mg J1572 Injection, immune globulin, (Flebogamma), intravenous, nonlyophilized (e.g., liquid), 500mg J1599 Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500 mg

Scientific Rationale

The term primary immunodeficiency denotes diseases resulting from inherited defects of the immune system. Multiple isolated defects and combined disorders have been described, including the combined immunodeficiencies, humoral immune deficiencies, and disorders resulting from phagocytic and complement defects. If left untreated, these infections may be fatal. The disorders constitute a spectrum of more than 80 innate defects in the body's immune system. Primary immunodeficiencies generally are considered to be relatively uncommon. There may be as many as 500,000 cases in the United States, of which about 50,000 cases are diagnosed each year. While most of these disorders present in childhood, characteristically after six months of age when maternal antibodies are lost, but they can also manifest later in life. Early recognition and diagnosis can alter the course of primary immunodeficiencies significantly and have a positive effect on patient outcome. Disorders of humoral immunity affect B-cell differentiation and antibody production. Collectively, these disorders account for approximately 50 percent of primary

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Posted: April 2011 immunodeficiencies. Typically, these patients develop infections with encapsulated bacteria. Recurrent bacterial sinus and pulmonary infections are the hallmark of antibody primary immunodeficiencies. Patients with humoral primary immunodeficiencies have an intact cellular immune system; thus, they are able to handle most viral and fungal pathogens, a factor that can help to distinguish these disorders clinically. In the United States, common variable immunodeficiency (CVID) is the most frequently diagnosed primary immunodeficiency. It is characterized by a low serum IgG level antibody deficiency at least 2 SDs below the mean for age, 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 to immunization with protein antigens (e.g., tetanus) or carbohydrate antigens (e.g., pneumococcal capsular polysaccharides such as pneumovax). Most patients experience severe recurrent and/or chronic sinopulmonary infections such as bronchitis, pneumonia, or bronchiectasis. Patients with CVID can also develop a variety of autoimmune and inflammatory disorders manifesting itself as chronic diarrhea, a sprue-like syndrome, inflammatory bowel disease, and joint involvement. Patients also have an enhanced risk of malignancy, especially non-Hodgkin's lymphoma. A number of studies have demonstrated that CVID can be reasonably managed with regular purified human immunoglobulin (IVIG) replacement that closely approximates normal physiological levels and prompt antibiotic therapy for acute bacterial infections. The current consensus is that IVIG replacement should be targeted at maintaining a trough level of > 500 mg/dL - the lower limit of normal. Of the primary immunodeficiency disorders, selective IgA deficiency may have the highest incidence, but the disorder is often asymptomatic and undiagnosed. Patients with symptoms often have sinusitis and respiratory tract infections, along with gastrointestinal involvement. Although serum IgA levels are below 5 mg per dL, serum IgG and IgM levels are in the normal range. In contrast to patients with common variable immunodeficiency, patients with IgA deficiency have a normal IgG response to vaccinations. Bruton's or X-linked agammaglobulinemia is caused by mutation or absence of the Bruton's tyrosine kinase gene. Early B-cell development is arrested, and serum immunoglobulins (IgG, IgA, IgM) are markedly deficient or totally absent. Onset of recurrent bacterial infections is usually at the end of the first year of life; however, patients with the disorder may not present until the age of three to five years. Primary immunodeficiency disorders caused by disruption of the cellular immune response with defects in T cells or both T and B cells are generally more severe than antibody deficiencies. Affected patients often present early in life with failure to thrive and disseminated infection. DiGeorge syndrome is one of the most recognized disorders in this category, and severe combined immunodeficiency is the most severe. General features of this class of diseases include overwhelming viral and fungal infections. Wiskott-Aldrich syndrome is an X-linked recessive syndrome characterized by thrombocytopenia, small platelets and platelet dysfunction, eczema, and susceptibility to infections. Infants typically present with prolonged bleeding from the circumcision site, bloody diarrhea, or excessive bruising. Patients with this primary immunodeficiency disorder are at risk for autoimmune diseases and cancer. Ataxia-

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Posted: April 2011 telangiectasia (Louis-Bar's syndrome) is a progressive neurologic disorder associated with cerebellar ataxia, oculocutaneous telangiectasias, chronic respiratory infections, a high incidence of malignancy, and variable humoral and cellular immunodeficiency. Patients with this disorder have difficulty walking and generally are wheelchair-bound by the teenage years. IVIG is a complex immunological product that contains neutralizing and opsonizing antibodies. The range of therapeutic activity is attributed to IVIG's myriad action mechanisms. IVIG can interact and bind onto complement factors, which can prevent complement-mediated tissue damage, modulate T-lymphocytes, alter cytokine profiles, increase antibactericidal activity by stimulating the phagocytic activity of leukocytes and modulate the immune system. These interactions can act alone or in combination to maintain immune balance while preserving homeostasis. In congenital or acquired hypogammaglobulinemia states, the mechanism of IVIG is relatively clear. IVIG can protect against infection by providing an adequate concentration of IgG. The dose is adjusted so that the trough level of serum IgG just before the next injection is at least 500 mg/dL, and perhaps higher. IVIG has replaced IM immune globulin for treatment of patients with primary immunodeficiency syndromes such as severe combined immunodeficiency (SCID) and common variable immunodeficiency. IVIG first was approved for patients with primary immunodeficiency diseases who exhibit severe impairment of antibody production, and its use in primary immunodeficiency patients with hypogammaglobulinemia (total IgG < 400 mg/dL) is well established. Patients with these conditions are at significant risk of developing serious and often life-threatening invasive infections. In patients with primary hypogammaglobulinemia, antibody replacement using IVIG is necessary to minimize complications associated with chronic sinusitis, bronchiectasis, and recurrent episodes of pyogenic pneumonia. Replacement therapy aims at maintaining an adequate level of serum IGs and, consequently, humoral immunity. Optimal serum levels usually are > 500 mg/dL (IgG total). Serum trough IgG levels must be monitored at appropriate intervals. The dosage and interval between IVIG infusions should be adjusted in accordance with the patient's clinical status and the serum trough levels to maintain levels between 400 and 600 mg/dl. Despite these remarkable improvements, patients continue to suffer from recurrent infections, progressive end organ damage, and chronic enteroviral meningitis. Although IVIG has provided remarkable advances in treating these disorders, the optimization of IVIG has not been investigated. Currently, there are no double-blind, placebo-controlled trials evaluating the effect of IVIG in primary immunodeficiency diseases. A number of studies have compared different doses in these patients. In all of the studies the higher dose has been shown to have greater therapeutic benefit, whether assessed as number of hospitalizations, as number of hospital days, or as incidence of specific infections such as pneumonia. Yet there is no study where 2 dosages have been compared and where patients receiving higher doses have been reported to have significantly improved outcomes. All controlled studies of IVIG administration in immune deficiency have demonstrated clear clinical benefits. These include a decreased incidence of bacterial upper and lower respiratory tract infection, reduced antibiotic use, fewer hospital admissions, improved pulmonary function, and improved growth and quality of life. Although there is no question relating to the usefulness of using IVIG replacement in primary immunodeficiency disorders, its role in patients with IgG subclass IVIG for Primary Immunodeficiencies Apr 11

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Posted: April 2011 deficiencies is not absolute and depends on the presence of specific antibody deficiencies. In patients with subclass deficiencies with concomitant recurrent or chronic respiratory infections, however, IVIG can provide significant benefits despite the fact that there has never been a double-blinded, placebo-controlled trial. Many patients with mild hypogammaglobulinemia, IgA deficiency, or IgG subclass deficiency can be managed successfully with antibacterial chemoprophylaxis. In many cases, this will be provided for relatively short periods of time (e.g., over a winter) for a few years. There are few published studies of antibiotic prophylaxis in these conditions. Some patients with more severe antibody deficiencies receiving IVIG infusions may also have an increased rate of bacterial infections at certain times (e.g., during the winter) and may also benefit from periodic antibiotic prophylaxis. There are no published controlled studies of the benefits of antibiotic prophylaxis in patients receiving IVIG. However, antibiotic prophylaxis provides clear benefit in hypogammaglobulinemic patients receiving intramuscular injections of gamma globulin. The severe combined immune deficiency (SCID) syndromes are a heterogeneous group of disorders arising from a disturbance in the development and function of both T and B cells. In some cases, the molecular defect prevents only T cell function, while B cells are normal. However, since B cells require signals from T cells to produce antibody, serious T cell dysfunction precludes effective humoral immunity. Natural killer cells, a lymphocyte subset exhibiting cytotoxic activities, may provide a degree of protection against bacterial and viral infections in patients with SCID since they develop via a pathway distinct from B and T cells, and are present in 50 to 70 percent of SCID patients. These cells may also provide some resistance to malignancy. The typical symptoms of SCID are recurrent severe infections, chronic diarrhea, and failure to thrive. Presentation is often in the newborn period, but may be delayed by several months since maternally-derived antibodies provide some early protection. The absence of both specific cellular and humoral immunity in patients with SCID leads to a profound susceptibility to many types of bacterial, viral infections and opportunistic organisms. Prophylaxis for Pneumocystis carinii pneumonia (PCP) should be administered to patients with severe combined immune deficiencies and patients receiving potent immunosuppressive therapy. PCP prophylaxis is also indicated in some other immunodeficiencies, such as X-linked hyper-IgM syndrome. Prophylactic regimens for PCP in primary and secondary immune deficiency are identical to those administered to patients with HIV infection. Patients with IgA and IgG subclass deficiency can often be managed without IVIG therapy. Although these patients may be susceptible to recurrent bacterial infection, these infections usually affect mucosal organs (sinopulmonary) and tend to be lowgrade and persistent rather than severe. For these patients, preventative measures combined with the appropriate antibiotic treatment can give satisfactory control of their symptoms. Chronic and recurrent sinopulmonary infections must also be treated aggressively with the appropriate antibiotics. Antibiotics should be started without delay and given at higher doses and for a longer duration when compared to treatment of the immunocompetent patient. For patients with chronic or frequent infections, low-dose prophylactic antibiotics may be appropriate. For many patients with mild to moderate immunodeficiency symptoms, conservative treatment with preventative measures and antibiotics provides good control of symptoms without IVIG therapy. Patient who fail to respond to these conservative measures may be considered for IVIG treatment. For patients who have severe

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Posted: April 2011 antibody deficiency, or for less severe patients whose symptoms have not been satisfactorily controlled by conservative measures, IVIG therapy is an effective safe treatment. Clinical response to IVIG therapy may vary among patients, therefore the IVIG dosage must be individualized for each patient. Any changes in the patient's symptoms should be correlated with the IgG kinetic studies. For severely antibody deficient patients, the starting IVIG dose is 400-mg/kg bodyweight once monthly. For patients with partial antibody deficiency, a reduced dosage of 100 - 200 mg/kg may be appropriate. The initial dosage should be given for 3 months before considering dosage adjustments based on improvement of symptoms, serum trough levels and adverse effects. The dosage adjustment could result in either an increase or decrease in dosage depending on theses parameters. The patient's maintenance IVIG dosage could result in a serum IgG level higher or lower than the "normal range" depending on the patient's clinical response to the IVIG therapy. The optimal IVIG dose is the lowest dose that provides the patient with consistent control of acute and chronic infections and also prevents progression of disease in the future. This dosage would also have the lowest risk of adverse effects.

Review History

January 2004 March 2006 April 2006 April 2008 April 2011

Medical Advisory Council initial approval Coding update Policy Update­ no revisions Code updates. No revision to policy Update ­ no revisions. Code Updates

English 1. MedlinePlus. Immune System and Disorders. Available at: http://www.nlm.nih.gov/medlineplus/immunesystemanddisorders.html Spanish 1. MedlinePlus. Enfermedades del sistema inmune. Available at: http://www.nlm.nih.gov/medlineplus/spanish/immunesystemanddisorders.html

Patient Education Websites

References ­ Update April 2011

1. 2.

3.

Ballow M, Notarangelo L, Grimbacher B, et al. Immunodeficiencies. Clin Exp Immunol. 2009 Dec;158 Suppl 1:14-22 Bayry J, Fournier EM, Maddur MS, et al. Intravenous immunoglobulin induces proliferation and immunoglobulin synthesis from B cells of patients with common variable immunodeficiency: a mechanism underlying the beneficial effect of IVIg in primary immunodeficiencies. J Autoimmun. 2011 Feb;36(1):9-15. Yong PL, Boyle J, Ballow M, et al. Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: A working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology. Clin Immunol. 2010 May;135(2):255-63. Quinti I, Soresina A, Spadaro G, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007 May;27(3):308-16. Bordigoni P. Immunoglobulin therapy of primary humoral immunologic deficiencies. Rev Prat. 2007 Oct 15;57(15):1691-8

References ­ Update April 2008

1. 2.

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Posted: April 2011 3. 4. 5. García JM, Español T, Gurbindo MD, et al. Update on the treatment of primary immunodeficiencies. Allergol Immunopathol (Madr). 2007 Sep-Oct;35(5):18492. Debes A, Bauer M, Kremer S. Tolerability and safety of the intravenous immunoglobulin Octagam: a 10-year prospective observational study. Pharmacoepidemiol Drug Saf. 2007 Sep;16(9):1038-47. Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies--a prospective, multi-national study. J Clin Immunol. 2006 Mar;26(2):177-85.

References

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Buckley RH. Primary cellular immunodeficiencies. J Allergy Clin Immunol 2002;109:747-57. Ballow M. Primary immunodeficiency disorders: antibody deficiency. J Allergy Clin Immunol 2002; 109:581-91. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 2002; 109:1001-4. Schinke, M, Izumo, S. Deconstructing DiGeorge syndrome. Nat Genet 2001; 27:238. Gelfand EW. Antibody-directed therapy: past, present, and future. JACI 2001;108(Suppl):S111-S116. Sacher RA et al. Intravenous immunoglobulin consensus statement. JACI 2001;108(Suppl):139-145. Sneller MC. Common variable immunodeficiency. Am J Med Sci 2001;321:4248. Gaspar HB, Kinnon C. X-linked agammaglobulinemia. Immunol Allergy Clin North Am 2001;21:23-43. Sacher RA; IVIG Advisory Panel. Intravenous immunoglobulin consensus statement. J Allergy Clin Immunol 2001;108(4 suppl):S139-46. Eijkhout HW et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. Ann Intern Med 2001;135:165-174. Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine 2000;79:155-69. Sorensen RU, Moore C. Antibody deficiency syndromes. Pediatr Clin North Am 2000;47:1225-52. Segal BH, Holland SM. Primary phagocytic disorders of childhood. Pediatr Clin North Am 2000;47: 1311-38. Frank MM. Complement deficiencies. Pediatr Clin North Am 2000;47:1339-54. Schwartz SA. Intravenous immunoglobulin treatment of immunodeficiency disorders. Pediatr Clin North Am 2000;47:1355-69. Chapel HM et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 2000;20:94-100. Schuval SJ. Treatment of antibody deficiency syndromes. Pediatr Rev 2000;21:358-359. Woroniecka M, Ballow M. Office evaluation of children with recurrent infection. Pediatr Clin North Am 2000;47:1211-1224. Sorensen RU, Moore C. Antibody deficiency syndromes. Pediatr Clin North Am 2000;47:1225-1252.

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Posted: April 2011 20. Schwartz SA. Intravenous immunoglobulin treatment of immunodeficiency disorders. Pediatr Clin North Am 2000;47:1355-1369. 21. Woroniecka M, Ballow M. Office evaluation of children with recurrent infection. Pediatr Clin North Am 2000;47:1211-24. 22. Paul ME, Shearer WT. The child who has recurrent infection. Immunol Allergy Clin North Am 1999; 19:423-36. 23. Nowak-Wegrzyn A, Lederman H. Supply, use, and abuse of intravenous immunoglobulin. Curr Opin Pediatr 1999;11:533-545. 24. Greenberg, PD, Riddell, SR. Deficient cellular immunity - Finding and fixing the defects. Science 1999; 285:546. 25. Conley, ME, Notarangelo, LD, Etzioni, A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol 1999; 93:190. 26. Kainulainen L et al. Pulmonary abnormalities in patients with primary hypogamma-globulinemia. JACI 1999;104:1031-1036. 27. Berger M. Goals of therapy in antibody deficiency syndromes. JACI 1999;104:911-913. 28. Quartier P et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr 1999;134:589-596. 29. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol 1999;93:190-7. 30. Ten RM. Primary immunodeficiencies. Mayo Clin Proc 1998;73:865-72. 31. Primary immunodeficiency diseases. Report of a WHO scientific group. Clin Exp Immunol 1997; 109 Suppl 1:1. 32. Levy, J, Espanol-Boren, T, Thomas, C, et al. Clinical spectrum of X-linked hyperIgM syndrome. J Pediatr 1997; 131:47. 33. Lacombe, C, Aucouturier, P, Preud'homme, J-L. Selective IgG1 deficiency. Clin Immunol Immunopathol 1997; 84:194. 34. Kornfeld, SJ, Haire, RN, Strong, SJ, et al. A novel mutation (Cys145-stop) in Bruton's tyrosine kinase is associated with newly diagnosed X-linked agammaglobulinemia in a 51-year-old male. Mol Med 1996; 2:619. 35. Farrar, JE, Rohrer, J, Conley, ME. Neutropenia in X-linked agammaglobulinemia. Clin Immunol Immunopathol 1996; 81:271. 36. Skull, S, Kemp, A. Treatment of hypogammaglobulinaemia with intravenous immunoglobulin, 1973-1993. Arch Dis Child 1996; 74:527. 37. Rudge, P, Webster, ADP, Revesz, T, et al. Encephalomyelitis in primary hypogamma-globulinaemia. Brain 1996; 119:1. 38. Kornfeld, SJ, Kratz, J, Haire, RN, et al. X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia of infancy. J Allergy Clin Immunol 1995; 95:915. 39. Rosen, FS, Cooper, MD, Wedgwood, RJP. The primary immunodeficiencies. N Engl J Med 1995; 333:431. 40. Fuleihan, R, Ramesh, N, Geha, RS. X-linked agammaglobulinemia and immunoglobulin deficiency with normal or elevated IgM: Immunodeficiencies of B cell development and differentiation. Adv Immunol 1995; 60:37. 41. Saffran, DC, Parolini, O, Fitch-Hilgenberg, ME, et al. A point mutation in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked agammaglobulinemia. N Engl J Med 1994; 330:1488.

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Posted: April 2011 42. Geha, RS and Rosen, FS. The genetic basis of immunoglobulin class switching. N Engl J Med 1994; 330:1008. 43. Sorensen RU, Moore C. Immunology in the pediatrician's office. Pediatr Clin North Am 1994;41: 691-714. 44. Wagner, JD, Stout, RD, Suttles, J. Role of the CD40-CD40 ligand interaction in CD4+ T cell contact-dependent activation of monocyte interleukin-1 synthesis. Eur J Immunol 1994; 24:3148. 45. Sullivan, KE, Mullen, CA, Blaese, RM, Winkelstein, JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr 1994; 125:876. 46. Herrod, HG. Management of the patient with IgG subclass deficiency and/or selective antibody deficiency. Ann Allergy 1993; 70:3. 47. Vetrie, D, Vorechovsky, I, Sideras, P, et al. The gene involved in X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases. Nature 1993; 361:226. 48. Lee, AH, Levinson, AI, Schumacher, HR Jr. Hypogammaglobulinemia and rheumatic disease. Semin Arthritis Rheum 1993; 22:252. 49. Barlan, IB, Geha, RS, Schneider, LC. Therapy for patients with recurrent infections and low serum IgG3 levels. J Allergy Clin Immunol 1993; 92:353. 50. Fuleihan, R, Ramesh, N, Loh, R, et al. Defective expression of the CD40 ligand in X-chromosome linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci U S A 1993; 90:2170. 51. Korthauer, U, Graf, D, Mages, HW, Briere, F. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 1993; 361:539. 52. Barlan, IB, Geha, RS, Schneider, LC. Therapy for patients with recurrent infections and low serum IgG3 levels. J Allergy Clin Immunol 1993; 92:353. 53. Notarangelo, LD, Duse, M, Ugazio, AG. Immunodeficiency with Hyper-IgM (HIM). Immunodefic Rev 1992; 3:101. 54. Sweinberg SK; Wodell RA; Grodofsky MP; et al. Retrospective analysis of the incidence of pulmonary disease in hypogammaglobulinemia. J Allergy Clin Immunol 1991 Jul;88(1):96-104. 55. Conley, MA, Buckley, RH, Hong, R, et al. X-linked severe combined immunodeficiency. Diagnosis in males with sporadic severe combined immunodeficiency and clarification of clinical findings. J Clin Invest 1990; 85:1548. 56. Cunningham-Rundles, C. Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Immunol 1989; 9:22. 57. Muller, W, Peter, HH, Kallfelz, HC, et al. The DiGeorge syndrome. II. Immunologic findings in partial and complete forms of the disorder. Eur J Pediatr 1989; 149:96. 58. Muller, W, Peter, HH, Wilken, M, et al. The DiGeorge syndrome. I. Clinical evaluation and course of partial and complete forms of the syndrome. Eur J Pediatr 1988; 147:496. 59. Ferreira, A, Garcia-Rodriguez, MC, Lopez-Trascasa, M, et al. IgA antibodies in selective IgA deficiency and in primary immunodeficient patients treated with gammaglobulin. Clin Immunol Immunopathol 1988; 47:199. 60. Ambrosino, DM, Umetsu, DT, Siber, GR, et al. Selective defect in the antibody response to Haemophilus influenzae type b in children with recurrent infections and normal serum IgG subclass levels. J Allergy Clin Immunol 1988; 81:1175. 61. Morgan, G, and Levinsky, RJ. Clinical significance of IgG subclass deficiency. Arch Dis Child 1988; 63:771.

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Posted: April 2011 62. Björkander, J, Hammarström, L, Smith, CIE, et al. Immunoglobulin prophylaxis in patients with antibody deficiency syndromes and anti-IgA antibodies. J Clin Immunol 1987; 7:8. 63. Swift, M, Morrell, D, Cromartie, E, et al. The incidence and gene frequency of ataxia telangiectasia in the united states. Am J Hum Genet 1986; 39:573. 64. Umetsu, DT, Ambrosino, DM, Quinti, I, et al. Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency. N Engl J Med 1985; 313:1247. 65. Hausser, C, Virelizier, JL, Buriot, D, et al. Common variable hypogammaglobulinemia in children. Am J Dis Child 1983; 137:833.

Important Notice General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net's National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language prevails. Medical policy is not intended to override the policy that defines the member's benefits, nor is it intended to dictate to providers how to practice medicine. Policy Effective Date and Defined Terms. The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for prior notification. If there is a discrepancy between the policy effective date and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. * In some states, new or revised policies require prior notice or posting on the website before a policy is deemed effective. For information regarding the effective dates of Policies, contact your provider representative. The Policies do not include definitions. All terms are defined by Health Net. For information regarding the definitions of terms used in the Policies, contact your provider representative. Policy Amendment without Notice. Health Net reserves the right to amend the Policies without notice to providers or Members. In some states, new or revised policies require prior notice or website posting before an amendment is deemed effective. No Medical Advice. The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. No Authorization or Guarantee of Coverage. The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service or supply. Members and providers should refer to the Member contract to determine if exclusions, limitations, and dollar caps apply to a particular procedure, drug, service or supply. Policy Limitation: Member's Contract Controls Coverage Determinations. The determination of coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the

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member's contract, and requirements of applicable laws and regulations. The contract language contains specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and other relevant terms and conditions of coverage. In the event the Member's contract (also known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member's contract shall govern. Coverage decisions are the result of the terms and conditions of the Member's benefit contract. The Policies do not replace or amend the Member's contract. If there is a discrepancy between the Policies and the Member's contract, the Member's contract shall govern. Policy Limitation: Legal and Regulatory Mandates and Requirements. The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. Policy Limitations: Medicare and Medicaid. Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid members shall not be construed to apply to any other Health Net plans and members. The Policies shall not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation.

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