Hypogammaglobulinemia

The term hypogammaglobulinemia refers to low immunoglobulin G (IgG), which may be mild or severe, and etiology may be characterized as primary (from low or absent B cell function) or secondary (due to excessive loss or rapid catabolism). Patients with low IgG may be asymptomatic, especially if the IgG is mildly below normal, or they may have a number of associated symtpms depending on the etiology of the low IgG. 

Hypogammaglobulinemia has varied causes and manifestations. It can be associated with a primary immune deficiency, be part of a multisystemic syndrome, or be secondary to other disorders. The common clinical feature of severe hypogammaglobulinemia is a predisposition toward infections that require antibody responses for irradication. These include but are not limited to 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.

In infants, hypogammaglobulinemia may be transient because of slow development of B-cell function, and is usually asymptomatic. ^[5]

Disorders of the immune system that can result in hypogammaglobulinemia can involve B cells, T cells, or both because protein antigens require T-cell recognition and T-cell help via cytokine signaling in order for B cells to produce antibodies. Some polysaccharide antigens do not require T-cell help for antibody production. ^[6]

The information in this article is not meant to be a comprehensive review of primary immune deficiency, 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 the more common forms of hypogammaglobulinemia.

Several codes in the International Classification of Diseases, 9th edition (ICD-9) relate to disorders in which hypogammaglobulinemia is a primary feature. These include deficiencies of humoral immunity, which is coded 279.0.

Immunoglobulins play crucial roles in the immune response by recognizing foreign antigens and triggering effector mechanisms and physiologic responses that attempt, and usually succeed, in eliminating the invading organism bearing that antigen. The human immune system is capable of producing up to 10⁹ different antibody species to interact with a wide range of antigens. The known immunoglobulin isotypes, named after their heavy-chains, 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 antibodies in serum, and IgA predominates in secretions. By binding to receptors for their Fc regions, 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. IgM, IgG1, IgG3, and, to a lesser degree, IgG2, fix and activate complement by the classical pathway. Most types of phagocytes bear receptors for the Fc of IgG.

In general, IgG1 is the major component of the response to protein antigens (eg, antitetanus and antidiphtheria antibodies). IgG2 and some IgG3 are produced in response to polysaccharide antigens (eg, antipneumococcal antibodies). Some patients who lack IgG2 still respond to polysaccharide antigens with the assistance of T cells and this is why vaccines against polysaccharide antigens are designed to utlize a protein conjugate to engage T-cell help. 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. This occurs mostly during the third trimester of pregnancy and provides the full-term infant with effective humoral immunity during the first months of life. The levels of maternal antibodies slowly fall because of catabolism, reaching nonprotective levels by about 6 months of age. During this time, the infant normally begins endogenous production of IgG. If endogenous production does not happen because of B-cell deficiency, infections will occur. ^{[6, 7]}

With the advent of serum protein electrophoresis, the globulins were considered to be comprised of 3 major fractions, alpha being the fastest moving and gamma the slowest. The gamma-globulin fraction is primarily composed of immunoglobulins, of which IgG is the largest component, constituting about 80% of the serum immunoglobulins in normal plasma, and is distributed throughout the entire volume of extracellular fluid. Immunoglobulins are produced by B cells that have matured into plasma cells.

Hypogammaglobulinemia may result from lack of production, excessive loss of immunoglobulins, or both. Congenital disorders affecting B-cell development can result in complete or partial absence of one or more Ig isotypes. The classic form of this type of disorder is Bruton agammaglobulinemia, also known as X-linked agammaglobulinemia (XLA). ^[8]  

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, although defects further down the differentiation pathways may result in deficiencies of a single cell type only. ^[9]

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 a restricted set of microorganisms primarily localized to the upper and lower airways, although bacteremia and GI infections can also occur. Patients with associated defects in cellular immunity usually present with opportunistic viral, fungal, or parasitic infections.

Normal catabolism of immunoglobulins occurs in a concentration-dependent manner, with higher concentrations being cleared faster. This phenomenon may have therapeutic implications: a specific, saturable Fc receptor (termed FcRn, which differs from phagocyte Fc receptors) is thought to promote cellular recycling of intact immunoglobulin molecules, preventing their catabolism by lysosomes and therefore prolonging their half-life in the circulation. Normal IgG molecules have a half-life of 21–28 days. Renal clearance usual 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.  

Renal loss of whole immunoglobulins occurs in nephrotic syndrome, in which albumin loss may be accompanied by immunoglobulin loss. Other types of acquired or secondary hypogammaglobulinemia include results of medications either intentional or as side effects (eg rituximab or corticosteroids versus phenytoin), gastrointestinal immunoglobulin loss, B-cell–related malignancies, and severe burns. Gastrointestinal loss occurs in protein-losing enteropathies and intestinal lymphangiectasia. Increased catabolism occurs in various diseases, including B-cell lineage malignancies and severe burns, but also in dystrophic myotonia.

For a detailed discussion of inherited causes of hypogammaglobulinemia, see Pure B-Cell Disorders.

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 two disorders is estimated to be 1 case in 700 persons and 1 case in 5000–10,000 persons of European ancestry, respectively. Selective IgM deficiency is a rare disorder. The incidence of agammaglobulinemia is approximately 1 in 200,000, and the incidence of severe combined immune deficiency (SCID) is approximately 1 in 50,000. ^{[10, 11]}

Mortality/morbidity

Morbidity and mortality will, of course, vary by the etiology of the hypogammaglobulinemia.

Patients with immune deficiencies resulting in hypogammaglobulinemia experience an increased incidence of a large spectrum of infections starting at an early age. Early identification and replacement of Ig will greatly alter the incidence of infection; for example,15% of untreated patients with X-linked agammaglobulinemia (XLA) die of infectious complications by age 20 years, but most have relatively normal life spans if they are diagnosed and begin immunoglobulin replacement therapy in early childhood, before chronic lung infection begins. ^[8]

In some types of CVID, which is a variable disorder with multiple genetic etiologies, patients are prone not only to infection but also immune dysregulation with increased risk of autoimmune disorders and cancer. ^{[12, 13, 14]}

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 SCID usually die before the second year of life if they do not receive allogeneic stem cell (bone marrow or cord blood) transplantation, while most patients with reticular dysgenesis die in early infancy. ^{[15, 16]} Most patients with Wiskott-Aldrich syndrome (WAS) die by the second decade of life if they do not undergo transplantation.

Although gene therapy, bone marrow transplantation, and immunoglobulin replacement with intravenous or subcutaneous immunoglobulin have had a significant impact on the natural history of these diseases, these require care at highly specialized centers.

Demographics

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

XLA, X-linked hyper-IgM syndrome, X-linked SCID, and WAS are X-linked disorders for which females are carriers and only males are affected. However, WAS may occur in female carriers if skewed inactivation of the X chromosome occurs, resulting in an active X chromosome carrying the Wiskott-Aldrich mutation.

CVID and IgA deficiency affect both sexes equally. Symptoms in XLA typically begin around 6 months of age, when the concentrations of maternal antibodies decline. However, this may vary considerably, depending in large part on the baby's exposure to other children carrying infectious organisms. Unfortunately, the diagnosis is often missed or delayed until significant morbidity has occurred. Some patients with atypical XLA mutations and others with autosomal hypogammaglobulinemia do not develop recurrent infections and laboratory abnormalities until adulthood and may be misdiagnosed with CVID or selective antibody deficiency.

Infections in SCID that is not detected by newborn screening, including severe candidiasis, pneumocystis jiroveci pneumonia, and cryposporidium, usually begin in the first months of life.

The symptoms of hyper-IgM syndromes usually begin during the first 2 years of life. Chronic cryptosporidia infection may be particularly problematic in X-linked hyper-IgM.

Patients with WAS start experiencing recurrent bacterial infections during the first year of life. 

Patients with reticular dysgenesis have loss of all leukocytes begin experiencing recurrent infections soon after birth. This ultimately leads to death in early infancy.

The age of onset of adenosine deaminase (ADA) deficiency is variable. Most patients are diagnosed during infancy and more are being diagnosed early because of newborn screening initiatives. ^[17] Because the failure of the immune system is gradual, some cases are not diagnosed until later childhood.

CVID has a variable age of onset, usually occurring by the third decade of life. However, on average, CVID patients experience increased infections and other symptoms for 10 years before their diagnosis is recognized. ^{[13, 14]}

Ig deficiency with thymoma (Good syndrome) affects adults aged 40–70 years.

Prognosis depends on etiology of hypogammaglobulinemia.

Prognosis for hypogammaglobulinemia secondary to excessive loss is dependent on treatment of causative disease.

Prognosis for hypogammaglobulinemia due to primary immune deficiency has improved significantly since the introduction of IVIG or SCIG therapy.

• Mortality due to overwhelming infections remains a major risk for patients with, although chronic progressive morbidity is more likely.

• Chronic lung and liver diseases result in significant morbidity and mortality.

• The risk of malignancy, especially lymphomas involving mucosal-associated lymphoid tissue, must be kept in mind.

• Autoimmune disease and cancer incidence is several-fold higher in immune deficiency patients than in matched controls.

• Severe combined immunodeficiency (SCID) is a true pediatric emergency that may not be apparent on the newborn physical examination. Newborn screening detects the vast majority of these patients so that survival is increased significantly because treatment with prophylactic immunoglobulin therapy and antibiotics followed by hematopoietic stem cell transplantation or gene therapy can be performed within the first 3 months of life before any infection occurs.  Without intervention, patients do not survive beyond early childhood. 

Educational information should emphasize treatment of causative conditions leading to hypogammaglobulinemia, or watchful waiting if no treatment is called for (eg transient hypogammaglobulinemia). If the hypogammaglobulinemia is secondary to another disease process, the patient may require information about why IVIG/SCIG is probably not indicated for renal and GI losses of IgG. If the hypogammaglobulinemia is secondary to a primary immune deficiency, the educational process will revolve around treatments and prophylaxis against infections.