Work Group Report of the American Academy of Allergy, Asthma & Immunology
Update on the use of immunoglobulin in human disease: A review of evidence

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Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted.

Section snippets

Primary immunodeficiency

Immunoglobulin replacement therapy via the IV or SC route is required in patients with certain PI diseases characterized by absent or deficient antibody production and, in most cases, recurrent or unusually severe infection (Table III).8, 9

Replacement therapy for agammaglobulinemia and hypogammaglobulinemia in well-described immunodeficiencies such as X-linked agammaglobulinemia (XLA) or common variable immunodeficiency (CVID) is necessary and life-saving. Other more genetically complex PIs,

Secondary immunodeficiency

IG therapy has also been used in a number of diseases that result in or potentially result in a secondary humoral immunodeficiency. This section discusses immunoglobulin use in CLL, multiple myeloma (MM), pediatric HIV infection, prematurity, geriatrics, genetic syndromes associated with immunodeficiency, and hypogammaglobulinemia following bone marrow transplantation and solid organ transplantation and in patients treated with B cell–depleting therapies.

Autoimmune diseases

IVIG has been used, with varying efficacy, in a number of systemic autoimmune disorders, as outlined in Table V and reviewed subsequently. These disorders are categorized into hematologic autoimmune diseases, rheumatic diseases, and organ-specific autoimmune diseases. The treatment approach to autoimmune diseases in general has significantly changed with the advent of newer biologic agents and immunomodulating therapies, minimizing the role for high-dose IVIG except in select situations.

Asthma

Asthma is a heterogeneous disorder characterized by chronic inflammation of the respiratory tract leading to airway hyper-responsiveness, airflow limitation, respiratory symptoms, and disease chronicity. Atopy is the strongest identifiable predisposing factor for developing asthma. In susceptible individuals, chronic airway inflammation causes recurrent episodes of wheezing, chest tightness, coughing, and excessive mucus production. Patients with these symptoms are occasionally found to have

Infectious and infection-related diseases

Despite improvements in antimicrobial therapies, there are a large number of pathogens that remain difficult to treat and others for which no specific chemotherapy exists. Thus, polyclonal immunoglobulin continues to be used for the treatment of a variety of infectious diseases and infection-related disorders (Table VI). Although there is significant anecdotal experience in a number of clinical settings, the cumulative evidence along with the cost-effectiveness and risks for complications must

Neurologic disorders

Despite the widespread use of IVIG in the treatment of a number of immune-mediated neurologic diseases, the consensus on its optimal use is insufficient. However, specialty-specific, evidence-based guidelines have recently been published.203, 384 IVIG has demonstrated some degree of effectiveness in a number of disorders of the peripheral and central nervous systems (Table VIII).

Miscellaneous uses

The utility of IVIG has been evaluated in a number of other conditions that have been proposed to result from an aberrant immunologic response (Table IX). Some of the reports are purely anecdotal, but others have been well designed and make a definitive statement regarding the use of IVIG in these conditions. Many of these diseases have few or no therapeutic alternatives, and warrant consideration of IVIG therapy based on the available evidence.

Practical considerations for immunoglobulin replacement therapy in antibody-deficiency diseases

A number of practical considerations in the use of IVIG (Table X) remain central toward facilitating patient therapy and improving the life experience of patients receiving IVIG. The safe and effective use of immunoglobulin requires attention to numerous issues that relate to the both the product and the patient. The administration of immunoglobulin, and the diagnosis and management of adverse events, are complex and demand expert practice. It becomes crucial for the prescribing physician to

Conclusion

Immunoglobulin therapy is essential for a broad array of diagnoses and can be clinically useful in many others. As immunoglobulin has diverse therapeutic mechanisms of action, the list of indications in which it is useful is likely to grow. Given the limited nature of this therapeutic agent, careful consideration of particular clinical indications is of the essence. Our recommendations do not relate to the severity of these particular diseases or to the potential for alternative therapies to be

References (658)

  • P.J. Busse et al.

    Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency

    J Allergy Clin Immunol

    (2002)
  • J. de Gracia et al.

    Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency

    Int Immunopharmacol

    (2004)
  • J. Levy et al.

    Clinical spectrum of X-linked hyper-IgM syndrome

    J Pediatr

    (1997)
  • P. Quartier et al.

    Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency

    Clin Immunol

    (2004)
  • M. Lucas et al.

    Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years

    J Allergy Clin Immunol

    (2010)
  • N. Shehata et al.

    The use of immunoglobulin therapy for patients with primary immune deficiency: an evidence-based practice guideline

    Transfus Med Rev

    (2010)
  • F.A. Bonilla et al.

    International Consensus (ICON) document: Common variable immunodeficiency disorders

    J Allergy Clin Immunol Pract

    (2016)
  • F.A. Bonilla et al.

    Practice parameter for the diagnosis and management of primary immunodeficiency

    Ann Allergy Asthma Immunol

    (2005)
  • J. Orange et al.

    Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology

    J Allergy Clin Immunol

    (2012)
  • M.J. Dorsey et al.

    Impaired specific antibody response and increased B-cell population in transient hypogammaglobulinemia of infancy

    Ann Allergy Asthma Immunol

    (2006)
  • B. Kaplan et al.

    Rituximab and immune deficiency: case series and review of the literature

    J Allergy Clin Immunol Pract

    (2014)
  • C. Cunningham-Rundles

    How I treat common variable immune deficiency

    Blood

    (2010)
  • I. Barlan et al.

    Therapy for patients with recurrent infections and low serum IgG3 levels

    J Allergy Clin Immunol

    (1993)
  • R. Rachid et al.

    The role of anti-IgA antibodies in causing adverse reactions to gamma globulin infusion in immunodeficient patients: a comprehensive review of the literature

    J Allergy Clin Immunol

    (2012)
  • F.A. Bonilla

    Intravenous immunoglobulin: adverse reactions and management

    J Allergy Clin Immunol

    (2008)
  • K.A. Sheerin et al.

    Antibody responses to protein, polysaccharide, and phiX174 antigens in the hypergammaglobulinemia E (hyper-IgE) syndrome

    J Allery Clin Immunol

    (1991)
  • M. Wakim et al.

    High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome

    Ann Allergy Asthma Immunol

    (1998)
  • H.D. Ochs et al.

    The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets

    Blood

    (1980)
  • K.E. Sullivan et al.

    A multiinstitutional survey of the Wiskott-Aldrich syndrome

    J Pediatr

    (1994)
  • M.E. Conley et al.

    An international study examining therapeutic options used in treatment of Wiskott-Aldrich syndrome

    Clin Immunol

    (2003)
  • C.M. Roifman et al.

    High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease

    Lancet

    (1987)
  • S. O'Brien et al.

    Advances in the biology and treatment of B-cell chronic lymphocytic leukemia

    Blood

    (1995)
  • H.M. Chapel et al.

    Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma

    Lancet

    (1994)
  • K. Sandberg et al.

    Preterm infants with low immunoglobulin G levels have increased risk of neonatal sepsis but do not benefit from prophylactic immunoglobulin G

    J Pediatr

    (2000)
  • D. Hefer et al.

    Thromboembolic events as an emerging adverse effect during high-dose intravenous immunoglobulin therapy in elderly patients: a case report and discussion of the relevant literature

    Ann Hematol

    (2004)
  • R. Hughes

    The role of IVIg in autoimmune neuropathies: the latest evidence

    J Neurol

    (2008)
  • European Federation of Neurological Societies and the Peripheral Nerve Society

    European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision

    J Peripher Nerv Syst

    (2010)
  • P. Dacci et al.

    Subcutaneous immunoglobulin therapy for the treatment of multifocal motor neuropathy: a case report

    Neurol Sci

    (2010)
  • T. Harbo et al.

    Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: a randomized, single-blinded cross-over trial

    Eur J Neurol

    (2009)
  • R.H. Buckley et al.

    The use of intravenous immune globulin in immunodeficiency diseases

    N Engl J Med

    (1991)
  • W. Al-Herz et al.

    Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency

    Front Immunol

    (2014)
  • H.M. Lederman et al.

    X-linked agammaglobulinemia: an analysis of 96 patients

    Medicine (Baltimore)

    (1985)
  • J.G. Liese et al.

    High- vs low-dose immunoglobulin therapy in the long-term treatment of X-linked agammaglobulinemia

    Am J Dis Child

    (1992)
  • F. Serana et al.

    The different extent of B and T cell immune reconstitution after hematopoietic stem cell transplantation and enzyme replacement therapies in SCID patients with adenosine deaminase deficiency

    J Immunol

    (2010)
  • C. Cunningham-Rundles et al.

    Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease

    Ann Intern Med

    (1984)
  • M.T. Nolte et al.

    Intravenous immunoglobulin therapy for antibody deficiency

    Clin Exp Immunol

    (1979)
  • K.M. Thickett et al.

    Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings

    QJM

    (2002)
  • J.A. Winkelstein et al.

    X-linked agammaglobulinemia: report on a United States registry of 201 patients

    Medicine (Baltimore)

    (2006)
  • J.A. Winkelstein et al.

    The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients

    Medicine (Baltimore)

    (2003)
  • H. Chapel et al.

    Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions

    Br J Haematol

    (2009)
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    Supported by educational grants from CSL Behring (grant no. 53347), Grifols (grant no. 002308), and Shire (formerly Baxalta BioScience; grant no. BT16-32525).

    Disclosures and potential conflicts of interest: M. Ballow has served on the data safety monitoring boards of Prometic and Green Cross; has received consulting fees from Baxalta; has received grant support from CSL Behring and Grifols; and has received lecture honoraria from Baxalta, Grifols, and CSL Behring. I. K. Chinn has received grant support from the Jeffrey Modell Foundation. J. Orange has received consulting fees from Baxalta, CSL Behring, Grifols, Walgreens, ADMA Biologics, and ASD Healthcare; has received grant support from CSL Behring; has received lecture honoraria from Baxalta; and has received royalties from UpToDate. E. Secord has received consulting fees from MDHHS; has received grant support from Wayne State University; and has received lecture honoraria from Hurly Hospital. R. Stiehm has received royalties from UpToDate. E. Perez has received consulting fees from Baxalta, CSL Behring, and Grifols; and has received royalties from UpToDate. T. Harville has received consulting fees from Baxalta. The rest of the authors declare that they have no relevant conflicts of interest.

    This Work Group Report, submitted by the Primary Immunodeficiency Diseases Committee, was approved by the AAAAI Board of Directors in November 2015.

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