Hypogammaglobulinemia

Background

Hypogammaglobulinemia is a clinicolaboratory entity with varied causes and manifestations. Several codes in the International Classification of Diseases, 9^th edition (ICD-9) relate to disorders in which hypogammaglobulinemia is a primary feature. These include deficiencies of humoral immunity, which is coded 279.0. The common clinical feature of hypogammaglobulinemia relates to a predisposition toward infections, which normally are defended against by antibody responses. These include Streptococcus pneumoniae and Haemophilus influenzae infections, which frequently involve the respiratory tract. While primary immunodeficiencies causing hypogammaglobulinemia are relatively uncommon, the demand for gammaglobulin treatment has grown and placed demands on the limited supply of this treatment. Therefore, an awareness of the appropriate diagnostic and therapeutic approaches to hypogammaglobulinemia is important.

Specific immune response is based on 2 major components, ie, (1) humoral immunity supported by B lymphocytes or B cells and (2) cellular immunity supported by T lymphocytes or T cells. Immunoglobulins (Igs) produced by B cells play a central role in humoral immunity, and deficiency may result in dramatic consequences for the body's defense against infections. Disorders of the immune system that can result in hypogammaglobulinemia can involve B cells, T cells, or both.

The finding of low levels of gammaglobulin is often of concern to the general pediatrician, as the particular form of immune deficiency is not immediately apparent. Furthermore, the prognosis of the particular immunologic derangement is not clear to the patient or her family. The typical causes of hypogammaglobulinemia are presented. The information in this article is not meant to be a comprehensive review but, rather, a guide on the differential diagnoses of hypogammaglobulinemia. This article provides a review of the causes, clinical symptoms, diagnosis, complications, and treatment of hypogammaglobulinemia.

Pathophysiology

Immunoglobulins play a dual role in the immune response by recognizing foreign antigens and triggering a biological response that attempts, and usually succeeds, to eliminate the antigen. The human immune system is capable of producing up to 10⁹ different antibody species to interact with a wide range of antigens. The 9 known isotypes, named after the heavy-chain isotype, are IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE.

The structural diversity of Ig isotypes is reflected in their functions. IgG isotypes represent the major component (approximately 85%) of all serum antibodies. By binding to the Fc receptors, they mediate many functions, including antibody-dependent cell-mediated cytotoxicity, phagocytosis, and clearance of immune complexes. IgM plays a pivotal role in the primary immune response. IgG1, IgG3, and IgM, and, to a lesser degree IgG2, fix and activate complement.

In general, IgG1 is the major component of the response to protein antigens (eg, antitetanus and antidiphtheria antibodies). IgG2 is produced in response to polysaccharide antigens (eg, antipneumococcal antibodies); however, some patients who lack IgG2 still respond to polysaccharide antigens. IgG3 seems to play an important role in the response to respiratory viruses. IgA and, to a lesser extent IgM, produced locally and secreted by mucous membranes, are the major determinants of mucosal immunity. IgG is the only Ig class that crosses the placenta to provide the infant with effective humoral immunity during the first 7-9 months of life. The levels of maternal antibodies slowly descend over 6-12 months. During this time, the infant begins endogenous production of IgG.

Serum gammaglobulins are primarily composed of immunoglobulins, of which IgG is largest component, constituting about 80% of the immunoglobulins. Immunoglobulins are produced by plasma cells. Catabolism of intravenous immunoglobulins occurs in a concentration-dependent manner, with higher concentrations being cleared faster. This phenomenon has therapeutic implications. Fc receptor function is thought to prevent excessive immunoglobulin catabolism by intracellular lysosomes. Normal renal clearance occurs for immunoglobulin fragments, not intact molecules. These fragments may be elevated in certain disease states and may be detected, for example, as myeloma-associated Bence Jones proteins in the urine.

Acquired or secondary hypogammaglobulinemia usually involves a few general categories. These include medications, renal loss of immunoglobulins, gastrointestinal immunoglobulin loss, B-cell–related malignancies, and severe burns. Renal loss of immunoglobulins is exemplified by nephrotic syndrome, in which IgG loss is usually accompanied by albumin loss. Gastrointestinal loss occurs in protein-losing enteropathies and intestinal lymphangiectasia. Increased catabolism occurs in various diseases, including the B-cell lineage malignancies and severe burns but also in dystrophic myotonia.

Hypogammaglobulinemia may result from lack of production, excessive loss of Igs, or both. Congenital disorders affecting B-cell development can result in complete or partial absence of one or more Ig isotypes. Because B, T, and natural killer (NK) cells share a common progenitor, defects occurring at early developmental stages may result in combined immunodeficiency involving all cell types.

Regardless of the primary cause, the symptoms depend on the type and severity of the Ig deficiency and the presence or deficiency of cellular immunity. In general, hypogammaglobulinemia results in recurrent infections with specific microorganisms primarily localized to the upper and lower airways. Patients with associated defects in cellular immunity usually present with opportunistic viral and fungal infections.

Frequency

The incidence of genetically determined immunodeficiency is relatively low when compared with acquired immunodeficiency. Humoral immunity deficiencies represent 50% of all primary immunodeficiencies. IgA deficiency is the most common antibody deficiency syndrome, followed by common variable immunodeficiency (CVID). The incidence of these 2 disorders is estimated to be 1 case in 700 persons and 1 case in 50,000-100,000 persons of European ancestry, respectively. Selective IgM deficiency is a rare disorder. IgG4 deficiency is very common and is detected in 10-15% of the general population. It usually does not cause hypogammaglobulinemia and usually is asymptomatic.

Mortality/Morbidity

Patients with hypogammaglobulinemia experience increased incidence of a large spectrum of infections starting at an early age.

• In many of these conditions, the risk of autoimmune disorders and cancer is increased, adding to the morbidity and mortality of infection. Recurrent infections may ultimately lead to significant end-organ damage, particularly involving the respiratory system.
• Patients with certain inherited disorders may not survive infancy or early childhood, and growth may be affected for those who survive. Patients with X-linked severe combined immunodeficiency (XSCID) die before the second year of life if they do not receive allogeneic bone marrow transplantation, while most patients with reticular dysgenesis die in early infancy. Of patients with X-linked agammaglobulinemia (XLA), 15% die of infectious complications by age 20 years. Most patients with Wiskott-Aldrich syndrome (WAS) die when aged approximately 11 years.
• Although intravenous Ig (IVIG) replacement, bone marrow transplantation, and gene therapy have had a significant impact on the natural history of these diseases, therapies are costly and require highly advanced facilities.

Race

No racial or ethnic predilection is recognized.

Sex

In children, primary immunodeficiencies are more common in boys than in girls (male-to-female ratio of approximately 5:1), while in adults, primary immunodeficiencies are diagnosed almost equally in both sexes (male-to-female ratio of approximately 1:1.4).

• Bruton disease, X-linked immunodeficiencies with hyper IgM, XSCID, and WAS are X-linked disorders for which females are carriers and only males are affected. However, WAS has been reported in a girl with skewed inactivation of the X chromosome resulting in an active X chromosome carrying the Wiskott-Aldrich mutation.
• CVID and IgA deficiency affect both sexes equally. They may be familial and frequently are associated with autoimmune disorders.

Age

• Symptoms in Bruton disease begin at age 7-9 months, after a significant decline of maternal antibodies. However, infections in XSCID begin in the first months of life.
• The symptoms of hyper IgM syndromes usually begin during the first 2 years of life.
• Patients with WAS start experiencing recurrent bacterial infections during the first year of life. The incidence of opportunistic infections, such as with Pneumocystis carinii, increases with time as patients survive childhood.
• Patients with reticular dysgenesis begin experiencing recurrent infections soon after birth, which ultimately leads to death in early infancy.
• The age of onset of adenosine deaminase (ADA) deficiency is variable. Most patients are diagnosed during childhood. Because the failure of the immune system is gradual, some cases are not diagnosed until early adulthood.
• IgA deficiency usually is asymptomatic in childhood, and many patients are diagnosed in early adulthood.
• CVID is characterized by varying age of onset, usually occurring by the third decade of life.
• Ig deficiency with thymoma (Good syndrome) affects adults aged 40-70 years.

Treatment

Medical Care

• IVIG replacement therapy is the treatment of choice for all primary immunodeficiency syndromes (except IgA deficiency), including Bruton disease, CVID, SCID, hyper IgM, and Wiskott-Aldrich syndrome (WAS).
• Patients with IgG subclass deficiency should not be given IVIG unless they fail to produce antibodies to protein and polysaccharide antigens and if they do not respond to prophylactic antibiotics.
• In selective IgA deficiency, IVIG therapy is not indicated. Oral administration of Ig may improve chronic diarrhea.
• Effort should be focused on the treatment of infections, allergic reactions, autoimmune diseases, and gastrointestinal diseases. Aggressive and prolonged antibiotic therapy covering S pneumoniae and H influenza is indicated. Due to the high frequency of G lamblia infection in these patients, an empiric course of metronidazole may result in dramatic improvement of the diarrhea and, to a certain extent, of malabsorption syndrome.
• The treatment of acquired hypogammaglobulinemia is directed at the underlying cause. Successful treatment of nephrotic syndrome, and protein-losing enteropathy, may result in improvement of Ig levels.
• IVIG is not indicated in the treatment of lymphoproliferative disorders, unless Ig levels are low in association with recurrent infections.
• Live vaccines (eg, bacille Calmette-Guérin, polio, measles, rubella, mumps) should not be given to patients (or their family members) with T-cell disorders, XLA, or other severe B-cell disorders. In patients with IgA deficiency, live vaccines are not an absolute contraindication if given intramuscularly.
• Interleukin-2 may improve in vitro lymphocyte function in patients with CVID.
• High doses of IVIG or intrathecal Ig may be beneficial in patients with enteroviral meningoencephalitis.
• Bone marrow transplantation is the treatment of choice for patients with SCID. More recently, the success with gene therapy in the treatment of certain patients with SCID revived the hope of definitive cure for these disorders.
• TNF inhibitors have been used to treat granulomatous diseases in patients with CVID.

Activity

Special restrictions on physical activity are not needed.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. The standard treatment for hypogammaglobulinemia is intravenous gammaglobulin (IVIG). IVIG is approved by the US Food and Drug Administration (FDA) for treatment of primary immunodeficiency disease or primary humoral immunodeficiency. As reviewed by the American Academy of Allergy, Asthma, and Immunology, 11 IVIG products are approved for this indication as of November 2005, and the benefit of this treatment for these primary immune deficiencies is based on category IIb evidence. IVIg is approved for only 2 secondary immune deficiencies: B-cell CLL and pediatric HIV. The use of IVIG for primary immune defects with normogammaglobulinemia and impaired specific antibody production is based on category III evidence only.

The usual IVIG dose is 0.4-0.6 g/kg every 3-4 weeks, titrating the dose and interval between infusions to achieve a trough IgG level greater than 500 mg/dL. Some practitioners target trough levels 300 mg/dL higher than pretreatment levels, and trough levels >800 mg/dL may improve pulmonary outcomes. Some centers administer a loading dose of 1g/kg if the patient is agammaglobulinemic.

Gammaglobulin may also be given intramuscularly or subcutaneously. The latter format is useful when allergic reactions limit the dose or rate. Subcutaneous gammaglobulin can be given with home infusions, usually requiring several hours of infusion. Intramuscular gammaglobulin injections were the standard of care before IVIG became readily available and are still useful in certain patients because of the simplicity of administration and fewer reactions. However, local injection site pain can be significant.

Up to 44% of patients report adverse reactions to IVIG that are not rate-related. Usually, the IVIG-associated reactions are anaphylactoid and include back pain, abdominal aching, nausea, rhinitis, asthma, chills, low grade fever, myalgias, and headaches. Renal failure is a less common but serious adverse reaction. Steroid, histamine blockers, and antipyretics can help treat or prevent the reactions, as can slowing the rate. Although most reactions occur during the first infusion, they may occur in repeat infusions of the same product. Although anti-IgA antibodies can be associated with increased reactions, most patients (regardless of anti-IgA antibody status) tolerate IVIG that is not depleted of IgA (IgA-depleted IVIG is available for treatment in patients who cannot tolerate IVIG that is not depleted of IgA).

Drug Category: Immunoglobulins

Improve clinical and immunologic aspects of the disease.

Drug Name	Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin, Gammar-P)
Description	Results in elevated antiviral or antibacterial antibody titers for 1 mo. Trough levels >500 mg/dL do not necessarily improve infection control except in certain long-standing infections but may significantly increase cost.
Adult Dose	200-400 mg/kg IV q3-4wk to achieve trough level of >400 mg/dL
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IgA deficiency
Interactions	Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccination)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Check serum IgA before IVIG (when absent, use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; lab result changes associated with infusions include 6-fold increase in ESR for 2-3 wk and apparent hyponatremia