Pediatric Annals

Special Issue Article 

Intravenous Immunoglobulin in the Treatment of Primary Immunodeficiency Diseases

Deirdre de Ranieri, MD; Nana Sarkoah Fenny, MD, MPH

Abstract

Intravenous immunoglobulin (IVIG) has been used as antibody replacement therapy in primary immunodeficiency diseases (PIDDs) for more than 50 years. Its role as a therapeutic agent has expanded over the past couple of decades as its anti-inflammatory and immune-modulatory mechanisms of action have been elucidated. It is now used “off-label” to treat other autoimmune diseases. This article focuses on the role of IVIG in the treatment of PIDDs characterized by absent or deficient antibody production. Replacement doses are given on a monthly basis in these conditions as a prophylactic measure to prevent acute and serious bacterial infections. [Pediatr Ann. 2017;46(1):e8–e12.]

Abstract

Intravenous immunoglobulin (IVIG) has been used as antibody replacement therapy in primary immunodeficiency diseases (PIDDs) for more than 50 years. Its role as a therapeutic agent has expanded over the past couple of decades as its anti-inflammatory and immune-modulatory mechanisms of action have been elucidated. It is now used “off-label” to treat other autoimmune diseases. This article focuses on the role of IVIG in the treatment of PIDDs characterized by absent or deficient antibody production. Replacement doses are given on a monthly basis in these conditions as a prophylactic measure to prevent acute and serious bacterial infections. [Pediatr Ann. 2017;46(1):e8–e12.]

The first report of the use of intravenous immunoglobulin (IVIG) in the treatment of agammaglobulinemia was written in 1952 by Ogden Bruton.1 Bruton described the case of an 8-year-old boy with a history of recurrent pneumococcal sepsis as well as an inability to mount antibody responses to several bacterial pathogens, including pneumococcus, diphtheria, and typhoid. This patient was found to have a complete absence of gamma globulin in his serum, and repletion with subcutaneous immune serum globulin resulted in complete resolution of his symptoms.1 The standard treatment regimen for patients with primary humoral immunodeficiencies is now lifelong IVIG replacement therapy. Furthermore, in the years since then, IVIG has been found to be beneficial in the treatment of numerous diseases, from primary humoral immune deficiencies, such as described above, to hematologic-oncologic processes, rheumatologic conditions, immune-mediated neurologic diseases, dermatologic conditions, and infections.

There are only six indications approved by the US Food and Drug Administration for the use of IVIG, and they include (1) replacement therapy in primary immunodeficiency diseases (PIDDs), (2) prevention of bacterial infections in B-cell chronic lymphocytic leukemia, (3) prevention of coronary artery disease in Kawasaki disease, (4) increasing platelet counts in idiopathic thrombocytopenic purpura, (5) treatment of multifocal motor neuropathy, and (6) treatment of chronic inflammatory demyelinating polyneuropathy (CIDP)2 (Table 1).


            FDA-Approved Uses of IVIG

Table 1.

FDA-Approved Uses of IVIG

However, IVIG is used off-label for many other indications, including juvenile dermatomyositis, juvenile polymyositis, autoimmune uveitis, thrombocytopenic purpura, cytomegalovirus-induced pneumonitis, staphylococcal toxic shock, Guillain-Barre syndrome, myasthenia gravis, autoimmune bullous disease, severe rheumatoid arthritis, and autoimmune diabetes mellitus.3 There has been an expansion in off-label use for IVIG in children and neonates over the past 15 years.3

There are currently more than 130 PIDDs, and in 2014, the International Union of Immunologic Societies stratified them into nine categories:4 (1) predominantly antibody deficiencies, (2) combined immunodeficiencies, (3) combined immunodeficiencies with associated or syndromic features, (4) congenital defects of phagocyte number and/or function, (5) complement deficiencies, (6) disorders of innate immunity, (7) diseases of immune dysregulation, (8) auto-inflammatory disorders, and (9) phenocopies of PIDDs.5

Antibody deficiencies (which account for more than half of all PIDDs) are characterized by a deficiency in one of the classes of antibodies, which include immunoglobulins (Ig) G, IgA, IgM, and IgE. Deficiency is defined as being less than 2 standard deviations below the normal value for that age. Levels should be compared to age-adjusted normal values, as they fluctuate with age.6 There are varying degrees of antibody deficiency (from none to mildly deficient) in these diseases. IVIG has been shown to be “beneficial” in primary immunodeficiencies with absent B cells, such as agamaglobulinemia, as well as primary immunodeficiencies characterized by hypogammaglobulinemia and impaired antibody responses to specific antigens, such as common variable immune deficiency (CVID), hyper-IgM syndrome, and ataxia telangiectasia.3 It is “probably beneficial” in primary immunodeficiencies with normogammaglobulinemia and impaired antibody responses to specific antigens,3 such as Wiskott-Aldrich syndrome.

Treatment

X-Linked Agammaglobulinemia

X-linked agammaglobulinemia, the most common cause of congenitial agammaglobulinemia, results from a mutation in the gene encoding Bruton tyrosine kinase (BTK). BTK promotes B cell development, and if not functioning properly, B cells will not progress past the pre-B cell stage. Affected males have low IgG, IgM, and IgA levels as well as a lack of antibody response to vaccines.6 Approximately one-quarter of patients also experience neutropenia. Children are usually somewhat shielded from disease manifestations until after age 4 to 6 months, secondary to circulating maternal antibodies. Most children present by age 2 years, usually with recurrent sinopulmonary infections;6,7 however, prior to diagnosis, recurrent episodes of acute otitis media are the most common symptom. Unfortunately, developing severe, life-threatening bacterial infections such as pneumonia, meningitis, or sepsis, often provides the impetus for the immune diagnostic testing. Other disease manifestations include enteritis, skin infections, and conjunctivitis. Antibody replacement with IVIG as well as chronic prophylactic antibiotics are the mainstay of therapy, with the goal of preventing bacterial infections and long-term sequelae of disease, such as chronic sinusitis and pulmonary disease.7

Common Variable Immunodeficiency

CVID is the most common PIDD. It is a heterogeneous disease that often presents in childhood with recurrent sinopulmonary infections. Diagnosis requires a history of recurrent or chronic bacterial infections, hypogammaglobulinemia, as well as ineffective response to vaccinations (Table 2). In children, the spectrum of illness can vary, but often includes recurrent infections of the upper and lower respiratory tracts, recurrent episodes of acute otitis media, severe infections such as bacterial meningitis, enteropathy, granulomatous disease, and autoimmune manifestations. These children often have significant reductions in IgG in combination with a low IgM and/or IgA.5,6 Bronchiectasis is one of the more common pulmonary complications of this disease, experienced by between 27% and 90% of patients, and is associated with recurrent lung infections.8 Gastrointestinal inflammation and poor growth are also manifestations of CVID, with more than one-quarter of patients experiencing decreased growth.5,9 Autoimmune manifestations include cytopenias, such as autoimmune hemolytic anemia and immune-mediated thrombocytopenia, as well as arthritis, gluten sensitive enteritis, and vasculitis. Malignancy is more frequent in adults with CVID, and approximately 20% develop cancer at some point, with lymphoma being the most common type.9 IVIG is effective in controlling severe infections in this disease, but often these patients continue to suffer from milder infections despite adequate prophylaxis.


            European Society for Immunodeficiencies Diagnostic Criteria for CVID

Table 2.

European Society for Immunodeficiencies Diagnostic Criteria for CVID

Ataxia-Telangiectasia

Ataxia-telangiectasia is an autosomal recessive disease characterized by progressive cerebellar ataxia and telangiectasia of the skin and conjunctiva, oculomotor ataxia, increased risk of malignancy, and recurrent infections. These patients typically have poor antibody responses to pneumococcal polysaccharide vaccines and often have low levels of immunoglobulins, including IgA, IgE, and IgG2.8 Alteration in the ATM (ataxia-telangiectasia mutated) gene results in the inability to recognize double-stranded breaks in DNA and the consequent lack of repair of these defects.6 Affected children develop progressive truncal and gait ataxia, slurred speech, choreoathetosis, and oculomotor apraxia. They usually require a wheelchair by age 10 years. Brain magnetic resonance imaging reveals atrophy of the frontal and posterior vermis as well as bihemispheric atrophy.8 There is a 40% increased risk of malignancy, the highest of any PIDD, which is thought to be secondary to an increased number of translocations due to double-stranded DNA breakages.3 IVIG is used in patients with severe infections and low levels of IgG. Steroids have been shown to temporarily ameliorate the central nervous system symptoms. Specialized chemotherapy is given for malignancy, to account for the slower DNA repair. Radiotherapy, if necessary, needs to be administered at much smaller doses and the patients closely monitored.8

Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS) is characterized by the triad of thrombocytopenia with small platelets, eczema, and recurrent infections. WAS is an X-linked recessive disease, caused by a mutation in the WAS protein gene, which plays a role in intracellular signaling and cell migration.10 This disease is quite rare, affecting 4 per 1 million males worldwide,11 and it usually presents in infancy, with manifestations of thrombocytopenia such as mucosal and gastrointestinal bleeding, purpura and petechiae, as well as eczema and recurrent bacterial and viral infections (usually acute otitis media). Although IgG levels are normal, specific antibody responses to both polysaccharide and protein vaccines are abnormal.3 Almost half of affected patients later develop autoimmune manifestations, most commonly autoimmune hemolytic anemia, arthritis, and vasculitis. There is an increased incidence of lymphoreticular malignancy in patients with WAS, and those with autoimmune manifestations are at higher risk.12 The spectrum of severity seen in WAS is wide, so management is tailored to the patient and their symptoms. Splenectomy is often indicated to treat thrombocytopenia, and the immunodeficiency is often treated with IVIG and prophylactic antibiotics, a combination that has been successful in decreasing infection rate in these patients.3 Bone marrow transplant is curative for the autoimmune component, provided there is an available human leukocyte antigen (HLA)-matched donor.11

Hyper-IgM Syndrome

Hyper-IgM syndrome is an immunodeficiency characterized by decreased levels of IgG and IgA and increased or normal levels of IgM. B cells are present but unable to generate appropriate antibody responses, secondary to a defect in isotype switching. It is inherited in either an autosomal recessive or X-linked manner. This disease is characterized by recurrent infections involving the upper and lower respiratory tracts, neutropenia, enteritis and oral ulcers, autoimmune disease, and malignancy. Children with this syndrome are treated similarly to those with agammaglobulinemia and require monthly IVIG replacement, which reduces the severity and frequency of infections.3,13

Mechanisms of Action

There are several different mechanisms of action through which IVIG exerts its therapeutic effects, from simple replacement therapy to immune modulation, depending on the dosage. In primary humoral immune deficiencies, it provides circulating immune globulin (mostly in the form of IgG), which can target a variety of microbes, including bacteria, viruses, mycoplasma, and parasites. It neutralizes and opsonizes these pathogens, thus bolstering host defenses.14 IVIG therapy used in this context decreases the incidence of respiratory and ear infections as well as pneumonia, meningitis, invasive bacterial infections, and bacterial sepsis. IVIG for this purpose is used at doses of approximately 400 to 600 mg every 3 to 4 weeks. Exact doses can vary, depending on metabolism, inter-current illness, and comorbid conditions, as well as the underlying disease (ie, severity of antibody deficiency), and higher doses are occasionally required to prevent pneumonia in certain groups.15–17 Interestingly, IVIG at higher doses (2 g/kg) functions in an immune-modulatory and anti-inflammatory capacity. Proposed actions include neutralization of autoantibodies via anti-idiotype antibodies, inhibition of complement-mediated damage, interaction with cells of the immune system, and modulation of cytokine levels, as well as Fc- and Fab-mediated mechanisms.14 Further description of these mechanisms is beyond the scope of this article but is nicely detailed elsewhere in the literature.14,18,19 When used at these higher doses, IVIG has been shown to be effective in several autoimmune diseases, such as immune thrombocytopenia purpura, Kawasaki disease, and juvenile dermatomyositis.18

Administration and Side Effects

Immune globulin was initially given intramuscularly, into the gluteus muscles, but is now given either intravenously or subcutaneously. Efficacy appears to be equivalent whether given subcutaneously or intravenously; however, adverse reactions are more common with the intravenous form, likely due to larger amounts getting infused over shorter time intervals. These adverse events include fever, chills, fatigue, myalgia, arthralgia, headache, nausea, and malaise. These symptoms are usually mild and reversible with rate reduction. Premedication with diphenhydramine and acetaminophen often decreases the severity of these reactions.19 Rare but serious adverse events include thromboembolism, acute hemolysis, anaphylaxis, transfusion-related lung injury, vasculitis, and acute renal failure. Aseptic meningitis is usually associated with high-dose IVIG and is not commonly seen in patients receiving replacement doses of immune globulin for PIDD. Sucrose-containing preparations increase the likelihood of having renal complications from IVIG administration.20 Infectious complications are also rare. IVIG is isolated from the pooled human plasma of between 1,000 and 10,000 donors, and is rigorously tested and treated to decrease the risk of transmitting infection. The larger bacterial products are normally filtered out, and the product is then subject to viral inactivation. IgE-mediated anaphylaxis is rare and usually occurs in IgA-deficient people (<5 mg/dL of serum IgA). It is estimated that approximately one-third of IgA-deficient people make antibodies to IgA, but only a small percentage of these have an anaphylactic reaction to IVIG. Although IgA content is purposefully depleted in these products, all products still contain trace amounts.19

Conclusion

IVIG is one of the mainstays of therapy in PIDD and is used primarily in a prophylactic manner to prevent recurrent infections and pneumonia. However, IVIG is also associated with better long-term outcomes in these patients. The rate of decline in lung function is lower in patients receiving IVIG, and there seems to be a dose-dependent effect, with increasing benefit seen at the higher end of the dose range.19 Studies to determine optimal and individualized dosing of IVIG depending on the disease type and severity as well as personal trough levels that keep patients free of infection are currently underway. The modern manufacturing process of IVIG had made its use increasingly safer and more convenient for patients.21

IVIG is an effective and well-tolerated therapy for patients with PIDDs. As the mechanisms are further delineated, it will likely benefit an increasing number of people with other autoimmune diseases.

References

  1. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722–728).
  2. US Food and Drug Administration. Immune globulin intravenous (IGIV) indications. http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasma-Products/ucm133691.htm. Accessed December 13, 2016.
  3. Orange JS, Hossny EM, Weiler CR, et al. Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma, and Immunology. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006;117(4):S525–S553. doi:10.1016/j.jaci.2006.01.015 [CrossRef]
  4. Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunologic Societies Expert Committee for Primary Immunodeficiency. Front Immunol. 2014;5(162):1–33.
  5. Beutler B, Casanova JL. New frontiers in immunology. Workshop on the road ahead: future directions in fundamental and clinical immunology. EMBO Rep. 2005;6(7):620–623. doi:10.1038/sj.embor.7400457 [CrossRef]
  6. Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allerg Immunol. 2014;46:154–168. doi:10.1007/s12016-014-8412-4 [CrossRef]
  7. Smith CI, Berglof A. X-linked agammaglobulinemia. April5, 2001 [Updated August 4, 2016]. In: Pagon RA, Adam MP, Ardinger HH, , eds. GeneReviews. Seattle, WA: University of Washington; 1993–2016. https://www.ncbi.nlm.nih.gov/books/NBK1453/. Accessed December 19, 2016,
  8. Gatti R, Perlman S. Ataxia-telangiectasia. March19, 1999 [Updated October 27, 2016]. In: Pagon RA, Adam MP, Ardinger HH, , eds. GeneReviews. Seattle, WA: University of Washington; 1993–2016. https://www.ncbi.nlm.nih.gov/books/NBK26468/. Accessed December 19, 2016.
  9. Abbott JK, Gelfand EW. Common variable immunodeficiency: diagnosis, management and treatment. Immunol Allergy Clin North Am. 2015;35(4):637–658. doi:10.1016/j.iac.2015.07.009 [CrossRef]
  10. Notorangelo ND, Miao CH, Ochs HD. Wiskott-Aldrich syndrome. Curr Opin Hematol. 2008;15:30–36. doi:10.1097/MOH.0b013e3282f30448 [CrossRef]
  11. Sullivan KE. Recent advances in our understanding of Wiskott-Aldrich syndrome. Curr Opin Hematol. 1999;6(1):8–14. doi:10.1097/00062752-199901000-00003 [CrossRef]
  12. Mortaz E, Tabarsi P, Mansouri D, et al. Cancers related to immunodeficiencies: update and perspectives. Frontiers Immunol. 2016;7(365):1–13. doi:10.3389/fimmu.2016.00365 [CrossRef]
  13. Qamar N, Fuleihan RL. The hyper IgM syndromes. Clin Rev Allerg Immunol. 2014;46:120–130. doi:10.1007/s12016-013-8378-7 [CrossRef]
  14. Kaveri SV. Intravenous immunoglobulin: exploiting the potential of natural antibodies. Autoimmun Rev. 2012;11:792–794. doi:10.1016/j.autrev.2012.02.006 [CrossRef]
  15. Bonagura VR. Using intravenous immunoglobulin (IVIG) to treat patients with primary immune deficiency disease. J Clin Immunol. 2013;33:S90–94 doi:10.1007/s10875-012-9838-1 [CrossRef]
  16. Berger M. Choices in IgG replacement therapy for primary immune deficiency diseases: subcutaneous IgG vs intravenous IgG and selecting an optimal dose. Curr Opin Allergy Clin Immunol. 2011;11(6):532–538. doi:10.1097/ACI.0b013e32834c22da [CrossRef]
  17. Quinti I, Soresina A, Guerra A, et al. IPINet Investigators. Effectiveness of immunoglobulin replacement therapy on clinical outcome in patients with primary antibody deficiencies: results from a multicenter prospective cohort study. J Clin Immunol. 2011;31:315–322. doi:10.1007/s10875-011-9511-0 [CrossRef]
  18. Pyne D, Ehrenstein M, Morris V. The therapeutic uses of intravenous immunoglobulins in autoimmune rheumatic diseases. Rheumatology. 2002;41:367–374. doi:10.1093/rheumatology/41.4.367 [CrossRef]
  19. Danieli MG, Gelardi C, Pedini V, Moretti R, Gabrielli A, Logullo F. Subcutaneous IgG in immune-mediate diseases: proposed mechanisms of action and literature review. Autoimmun Rev. 2014;13(12):1182–1888. doi:10.1016/j.autrev.2014.08.018 [CrossRef]
  20. Katz U, Achiron A, Sherer Y, Shoenfeld Y. The safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev. 2007;6(4):257–259. doi:10.1016/j.autrev.2006.08.011 [CrossRef]
  21. Bonagura VR. Illustrative cases on individualizing immunoglobulin therapy in primary immunodeficiency disease. Ann Allergy Asthma Immunol. 2013;111:S10–S13. doi:10.1016/j.anai.2013.09.014 [CrossRef]
  22. European Society for Immunodeficiencies. New clinical diagnosis criteria for the ESID Registry. http://esid.org/Working-Parties/Registry/Diagnosis-criteria. Accessed December 19, 2016.

FDA-Approved Uses of IVIG

<list-item>

Primary humoral immunodeficiency

</list-item><list-item>

Immune thrombocytopenic purpura

</list-item><list-item>

Kawasaki disease

</list-item><list-item>

Multifocal motor neuropathy

</list-item><list-item>

B-cell chronic lymphocytic leukemia

</list-item><list-item>

Chronic inflammatory demyelinating polyneuropathy

</list-item>

European Society for Immunodeficiencies Diagnostic Criteria for CVID

Must be at least 4 years old and have <list-item>

One or more of the following <list-item>

Increased susceptibility to infection

</list-item><list-item>

Granulomatous disease

</list-item><list-item>

Signs of autoimmunity

</list-item><list-item>

Unexplained polyclonal lymphoproliferation

</list-item><list-item>

Antibody deficiency in an affected family member

</list-item>

</list-item><list-item>

Antibody levels <list-item>

IgG, IgA >2 SD below mean for age

</list-item><list-item>

IgM >2 SD below mean for age (not mandatory)

</list-item>

</list-item><list-item>

And either <list-item>

Poor vaccine response and absent hemagglutinins

or

</list-item><list-item>

Low-switched memory B cells

</list-item> And not any of the following <list-item>

Low or absent CD4 numbers

</list-item><list-item>

Absent T-cell proliferation

</list-item> Pathologic findings (not mandatory) <list-item>

Lymphoid interstitial pneumonitis

</list-item><list-item>

Granulomatous disorder

</list-item><list-item>

Nodular regenerative hyperplasia of the gut

</list-item><list-item>

Nodular regenerative hyperplasia of the liver

</list-item><list-item>

Absence of plasma cells on gut biopsy

</list-item> Secondary causes must be ruled out <list-item>

Infection

</list-item><list-item>

Renal protein loss

</list-item><list-item>

Protein losing enteropathy

</list-item><list-item>

Genetic syndromes

</list-item><list-item>

Immunosuppressive medications

</list-item><list-item>

Other medications

</list-item><list-item>

Malignancy

</list-item>

</list-item>
Authors

Deirdre De Ranieri, MD, is an Attending Physician, Section of Pediatric Rheumatology, Comer Children's Hospital; and an Assistant Professor of Pediatrics, The University of Chicago. Nana Sarkoah Fenny, MD, MPH, is an Attending Physician, Section of Allergy and Immunology, Comer Children's Hospital; an Assistant Professor of Pediatrics and an Assistant Professor of Medicine, The University of Chicago Medicine; and an Attending Physician, Section of Pulmonary/Critical Care, The University of Chicago Medicine.

Address correspondence to Deirdre De Ranieri, MD, The University of Chicago Medicine, 5841 South Maryland Avenue, MC 5044, Chicago, IL 60637; email: dderanieri@peds.bsd.uchicago.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20161213-03

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