Hypogammaglobulinemia

Hypogammaglobulinemia has varied causes and manifestations. It can be associated with a primary immune deficiency, be part of a multi-systemic syndrome, or be secondary to other disorders. 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. The common clinical feature of severe hypogammaglobulinemia is a predisposition toward infections that normally are defended against by antibody responses. 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.

Specific or adaptive immune responses are based on 2 major components, ie, (1) humoral immunity, involving antibodies produced by B lymphocytes also known as B cells, and (2) cellular immunity, requiring recognition 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, because protein antigens require T cell recognition and help via cytokine signaling, in order for B cells to produce antibodies. Some polysaccharide antigens do not require T cell help for antibody production.

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 the more common forms of hypogammaglobulinemia.

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. 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 begins endogenous production of IgG.

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 plasma cells.

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 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. The major types 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 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).

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.

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.

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 2 disorders is estimated to be 1 case in 700 persons and 1 case in 5,000–10,000 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 clinical hypogammaglobulinemia and usually is asymptomatic.

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 many have relatively normal life spans if they are diagnosed and begin immunoglobulin replacement therapy in early childhood, before chronic lung infection begins. 

In some types of CVID, which is a variable disorder with multiple genetic etiologies, patients are prone not only to infection, but also increased risk of autoimmune disorders and cancer. ^{[3, 4]} 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 severe combined immunodeficiency (SCID) die before the second year of life if they do not receive allogeneic stem cell (bone marrow or cord blood) transplantation, ^[1] while most patients with reticular dysgenesis die in early infancy. Most patients with Wiskott-Aldrich syndrome (WAS) die by the second decade of life if they don't 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 therapies are costly and often require highly advanced facilities.

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 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. ^[5] 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. The incidence of opportunistic infections, such as Pneumocystis jiroveci, increases with time as patients survive childhood.

Patients with reticular dysgenesis 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. 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.

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