Hypogammaglobulinemia

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Practice Essentials

Hypogammaglobulinemia refers to a set of clinicolaboratory entities with varied causes and manifestations. The common clinical feature of hypogammaglobulinemia relates to a predisposition toward infections that normally are defended against by antibody responses (including Streptococcus pneumoniae and Haemophilus influenzae infections).

Signs and symptoms

Most patients with hypogammaglobulinemia present with a history of recurrent infections. A detailed clinical history should emphasize the following:

Physical findings may include the following:

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies that may be helpful include the following:

Imaging studies that may be useful include the following:

The following tests may be considered as circumstances warrant:

The following biopsy procedures may also be considered:

See Workup for more detail.

Management

Replacement therapy with immunoglobulin G (IgG), administered intravenously (IVIG) or subcutaneously (SCIG), is the treatment of choice for most primary immunodeficiency syndromes, including the following:

Treatment of secondary hypogammaglobulinemia is directed at the underlying cause, as follows:

See Treatment and Medication for more detail.

Background

Hypogammaglobulinemia refers to a set of clinicolaboratory entities with varied causes and manifestations. 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 hypogammaglobulinemia relates to a predisposition toward infections that 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 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.

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.

Pathophysiology

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.

Epidemiology

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

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

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). In adults, primary immunodeficiencies are diagnosed almost equally in both sexes (male-to-female ratio of approximately 1:1.4).

Age

See the list below:

History

Most patients with hypogammaglobulinemia present with a history of recurrent infections. A detailed clinical history should emphasize the following:

Family history

A positive family history may suggest the diagnosis and guide testing, but a negative family history does not exclude X-linked agammaglobulinemia (Bruton agammaglobulinemia; XLA), as new mutations may constitute more than half of the cases in some series.[5]

A family history of a male infant with severe combined immunodeficiency (SCID) should suggest prompt testing of subsequent male infants.

Age of onset

Onset during early childhood suggests an inherited disorder. However, the condition transient hypogammaglobulinemia of infancy, as its name implies, represents a delay in the maturation of the full range of antibody responses, and usually resolves by a few years of age.

Acquired hypogammaglobulinemias may start at any age, depending on the underlying cause (see Age).

Site of infections

The site of infections may provide clues to the significance and the type of immune deficiency. The specific system infections and symptoms are discussed in this section.

Type of microorganisms

Antibody deficiency and complement deficiency are associated with recurrent infections with encapsulated bacteria. These most often involve the respiratory tract, including otitis media, and may lead to bronchiectasis in childhood. Giardia lamblia infection is frequently observed in patients with combined variable immunodeficiency (CVID) or IgA deficiency.

Opportunistic infections with viral, fungal, or protozoan pathogens suggest concomitant T-cell deficiency, although some of these pathogens can occasionally cause infections with CVID and XLA.

Blood product reactions

History of anaphylaxis or other severe reactions following transfusion of blood products may indicate an underlying IgA deficiency.

Rarely, patients with undetectable IgA antibodies may develop anti-IgA antibodies of the IgE isotype. Once sensitized, these patients are at risk for anaphylactic reactions if they receive blood products containing even small amounts of IgA. Most patients who have anaphylactic reactions to blood transfusions, however, do not have IgA deficiency, and most patients with IgA deficiency do not develop IgE anti-IgA antibodies.

Recurrent infections

Infections (in decreasing order of occurrence) commonly affect the upper and lower respiratory tracts (eg, sinopulmonary infections, including chronic otitis media, sinusitis, bronchitis/bronchiectasis, pneumonia), gastrointestinal tract (eg, bacterial or parasitic gastroenteritis), skin, joints, and meninges. Septicemia, conjunctivitis, and osteomyelitis are less common.

Encapsulated bacteria such as S pneumoniae, Streptococcus pyogenes, H influenzae, and Staphylococcus aureus are the most common pathogens. Bordetella pertussis may rarely play an important role in respiratory infections.

IgG2 is the predominant isotype of antibodies produced in response to polysaccharides. Thus, occasionally isolated IgG2 deficiency may be as severe as global IgG deficiency in terms of recurrent upper and lower respiratory tract infections with encapsulated bacteria. Isolated IgG3 deficiency may be associated with recurrent sinopulmonary infections with viruses and Moraxella catarrhalis, and with pneumococcal infection, in a few patients .

In pure B-cell disorders, cellular immunity generally is intact, and the frequency of opportunistic fungal and mycobacterial infections is not increased. However, note that in X-linked hyper-IgM syndrome, for example, a T-cell defect is responsible for a lack of B-cell isotype switching. The lack of IgG and IgA are the hallmarks of this disease, but fungal and protozoan infections are often responsible for more severe morbidity than bacterial infections since the latter are largely preventable by IgG replacement therapy. In combined B-cell and T-cell disorders, both components of the immune response are defective, which leads to mixed presentation, including increased infections with encapsulated bacteria and infections with fungi, Mycobacterium species, and P carinii. Occasionally, severe and prolonged primary varicella (or zoster), herpes simplex, andcytomegalovirus infections may occur.

Patients with XLA are typically infected with pneumococcal, streptococcal, or staphylococcal organisms and H influenzae. While the upper respiratory system, conjunctivae, and gastrointestinal tract are the usual sites of infection, patients with no antibodies are prone to bacteremia and sepsis, as well. Infections are typically seen when patients are younger than 5 years, but the diagnosis is often delayed. XLA may present with neutropenia, since the affected enzyme is also involved in myeloid development.[5]

Without IgG replacement, patients with XLA are also susceptible to viral diseases that were common in childhood before widespread immunization, including measles, mumps, rubella and polio. The typical invasive bacteria seen in XLA are found in hyper-IgM syndrome, as well. These patients can also be susceptible to P carinii infection, which may represent the initial presentation of an immunodeficiency. These patients usually exhibit increased susceptibility when younger than 5 years, but atypical XLA patients may be asymptomatic until adulthood.

Although most patients with IgA deficiency are healthy, some patients develop symptoms later in life after an uneventful childhood and early adulthood. Recurrent or chronic upper and lower respiratory tract infections leading to bronchiectasis, chronic sinusitis or cor pulmonale are not common.

Although cellular immunity generally is intact in common variable immunodeficiency (CVID), occasional cases of severe abnormalities of cell-mediated immunity have been reported. In these cases, infections with fungi, mycobacteria, and P carinii may be seen, and severe and prolonged primary varicella or herpes zoster, herpes simplex, and cytomegalovirus infections have been reported.

Recurrent and life-threatening infections with encapsulated bacteria, particularly pneumococcal and meningococcal infections, characterize the rare disorder of selective IgM deficiency.

During the first years of their lives, patients with transient hypogammaglobulinemia of infancy may have a high incidence of recurrent upper respiratory or gastrointestinal infections, but they do not usually have life-threatening or opportunistic infections.

Half the patients with Good syndrome (immunodeficiency with thymoma) have cell-mediated immunodeficiency and may present with mucocutaneous candidiasis, cytomegalovirus, herpes zoster, or P carinii.

Patients with disorders of T-cell maturation and/or function, including ADA deficiency, may develop disseminated infection with the attenuated viruses used in live virus vaccines. Such immunizations should be withheld from these infants, and exposure to chicken pox should be avoided.

Gastrointestinal symptoms

Diarrhea with malabsorption syndrome is reported in more than 50% of patients.

Gastritis with achlorhydria and pernicious anemia may occur.

G lamblia and Campylobacter species are the pathogens involved in the gastrointestinal manifestations in many of these patients.

Other gastrointestinal diseases, such as sprue-like syndrome, ulcerative colitis, and Crohn disease, have been reported in patients with CVID and IgA deficiency.

Chronic cholangitis and hepatitis with Cryptosporidium parvum is often associated with X-linked hyper-IgM syndrome.

Musculoskeletal symptoms

Arthralgia and monoarticular or oligoarticular arthritis of the large joints with sterile effusions occasionally occur. Ureaplasma urealyticum has been implicated in the pathogenesis of "sterile" arthritis.

In many cases, acute septic arthritis may occur after recognized or unrecognized bacteremia.

Autoimmune and collagen vascular diseases

The incidence of autoimmune and collagen vascular diseases is increased, especially in IgA deficiency. Rheumatoid arthritis, systemic lupus erythematosus without renal disease, autoimmune hepatitis, neutropenia, hemolytic anemia, and endocrinopathies have been described, especially in CVID.[4, 6]

Pure red cell aplasia, agranulocytosis, and myasthenia gravis have been reported with Good syndrome.

Reactions to blood products

IgE-mediated anaphylactic reactions to the IgA contained in blood products have been reported to rarely occur in patients with complete IgA deficiency.

In addition, a patient's IgG anti-IgA may form immune complexes with infused IgA. These immune complexes then activate complement and can initiate anaphylactoid reactions due to mast cell activation by C3a and C5a. IgG anti-IgA frequently cause transfusion reactions if patients deficient in IgA are given plasma or whole blood. Washed packed cells should be used to avoid this problem.

Physical

See the list below:

Causes

Hypogammaglobulinemia may be caused by primary (congenital) or secondary (acquired) disorders. The following lists of key disorders are not meant to be exhaustive. Note that primary disorders, which may be inherited or due to spontaneous mutations, may not present clinically until later in life, even though the gene defect is present since birth. Thus, most cases of XLA do not present before 6 months of age; most cases of CVID, which do not present until the third or fourth decade of life, are considered primary immune deficiencies and are presumed to be due to as yet undiscovered gene defects.

Laboratory Studies

See the list below:

Imaging Studies

See the list below:

Other Tests

See the list below:

Histologic Findings

See the list below:

Medical Care

See the list below:

Activity

Special restrictions on physical activity are not needed.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. The standard treatment for hypogammaglobulinemia is IgG replacement, which may be given intravenously or subcutaneously.[9, 10, 21] IgG preparations are approved by the US Food and Drug Administration (FDA) for treatment of primary immunodeficiency disease (primary humoral immunodeficiency) and a few additional indications, but considerable amounts of intravenous immunoglobulins (IVIG) are used "off label" for other conditions.[9, 21]

As reviewed by the American Academy of Allergy, Asthma, and Immunology, the benefit of IgG treatment for these primary immune deficiencies is based on category IIb evidence (13).[9] IVIG is approved for only 2 secondary immune deficiencies: B-cell chronic lymphocytic leukemia (B-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.[9]

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. Usual total monthly doses of subcutaneous IgG (SCIG) are in the same range, given as 100-200 mg/kg/wk. 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.[9, 10, 21]

Gammaglobulin may also be given intramuscularly or subcutaneously.[21] The latter format is useful when allergic reactions limit the dose or rate, but it is becoming increasingly popular even when these problems are not present. SCIG can be given at home by parents or by patients themselves, 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, and the doses that can be given this way are limited.

Up to 44% of patients report adverse reactions to IVIG. These most commonly respond to decreasing the rate of the Ig infusion. Usually, the IVIG-associated reactions are infusion-related 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 that was predominately caused by sucrose-containing lyophilized IgG preparations that are no longer available in the United States. Infusion rate reduction, systemic steroids, histamine blockers, and antipyretics or nonsteroidal anti-inflammatory drugs (NSAIDs) can help treat or prevent the reactions.

Although the incidence of reactions is highest 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 (low-IgA products should be selected for treatment in patients who cannot tolerate IVIG that is not depleted of IgA). Thrombosis, myocardial infarction, hemolytic anemia, hyperviscosity syndrome, and aseptic meningitis are uncommon but reported adverse events.

Immune globulin IV (IGIV; Bivigam, Carimune NF, Gammagard, Gammaplex, Cuvitru, Gammaked, Gammaplex, Octagam, Privigen)

Clinical Context:  Replacement therapy for primary and secondary immunodeficiencies and IgG antibodies against bacteria, viral, parasitic and mycoplasma antigens.

Therapy 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.

Class Summary

Agents in this class improve clinical and immunologic aspects of the disease.

Pneumococcal vaccine polyvalent (Pneumovax 23)

Clinical Context:  Inactive bacterial vaccine that induces active immunization to the serotypes contained in the vaccine.

Pneumococcal vaccine 13-valent (Prevnar 13)

Clinical Context:  Promotes active immunity against S. pneumoniae capsular serotypes 1,3,4,5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, which are all conjugated to CRM197 protein.

Class Summary

Polyvalent pneumococcal vaccine (PPV-23) protects against 23 serotypes of S pneumoniae; approximately 70% of invasive diseases caused by S pneumoniae result from these serotypes.

Pneumococcal 13-valent conjugate vaccine (PCV-13) protects against the 13 serotypes of S pneumoniae that cause the most severe pneumococcal infections in children.

Further Outpatient Care

See the list below:

Inpatient & Outpatient Medications

See the list below:

Transfer

See the list below:

Deterrence/Prevention

See the list below:

Complications

See the list below:

Prognosis

See the list below:

Patient Education

See the list below:

Author

Amit J Shah, MD, Allergist/Immunologist, Asthma and Allergy Clinic of Utah, Salt Lake City, UT

Disclosure: Nothing to disclose.

Coauthor(s)

Jenny Shliozberg, MD, Associate Clinical Professor, Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine; Consulting Staff, Department of Pediatrics, Montefiore Hospital Medical Center and Albert Einstein College of Medicine; Director of Pediatric Allergy and Immunization Clinic, Children's Hospital at Montefiore Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Michael R Simon, MD, MA, Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Professor, Department of Internal Medicine, Oakland University William Beaumont University School of Medicine; Adjunct Staff, Division of Allergy and Immunology, Department of Internal Medicine, William Beaumont Hospital

Disclosure: Have a 5% or greater equity interest in: Secretory IgA, Inc. ; siRNAx, Inc.<br/>Received income in an amount equal to or greater than $250 from: siRNAx, Inc.

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Disclosure: Nothing to disclose.

Additional Contributors

Melvin Berger, MD, PhD, Adjunct Professor of Pediatrics and Pathology, Case Western Reserve University; Senior Medical Director, Clinical Research and Development, CSL Behring, LLC

Disclosure: Received salary from CSL Behring for employment; Received ownership interest from CSL Behring for employment; Received consulting fee from America''s Health insurance plans for subject matter expert for clinical immunization safety assessment network acvtivity of cdc.

Robert Y Lin, MD, Professor, Department of Medicine, New York Medical College; Chief, Allergy and Immunology, and Director of Utilization Review, Department Medicine, New York Downtown Hospital

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors James O Ballard, MD, Issam Makhoul, MD, and Avi M Deener, MD, to the development and writing of this article.

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