Hypogammaglobulinemia 

Updated: Dec 26, 2018
Author: Elizabeth A Secord, MD; Chief Editor: Michael A Kaliner, MD 

Overview

Practice Essentials

Hypogammaglobulinemia refers to a laboratory finding (low immunoglobulin G, or IgG) that may be asymptomatic if mild or may be associated with a number of clinical entities with varied causes and manifestations if more extreme. IgA deficiency is a separate diagnosis, but may be a precursor to loss of IgG, or may occur concurrently. Hypogammaglobulinemia may be due to a primary immune deficiency or may be secondary to other disease entities. The common clinical feature of symptomatic hypogammaglobulinemia is a predisposition toward infections that normally are defended against by antibody responses (including but not limited to Streptococcus pneumoniae and Haemophilus influenzae infections). The source of the immunoglobulin deficiency is key, as the treatment will vary by causality.

Signs and symptoms

Patients with mild hypogammaglobulinemia (slightly low Immunoglobulin) may be asymptomatic, but those with more severe hypogammaglobulinemia usually present with a history of recurrent infections. A detailed clinical history should emphasize the following:

  • Reason for lab draw that defined the abnormality

  • Symptoms (especially infections)

  • Age of onset

  • Family history

  • Site of infections

  • Type of microorganisms

  • Recurrent infections

  • Gastrointestinal symptoms

  • Musculoskeletal symptoms

  • Autoimmune and collagen vascular diseases

Physical findings will vary by etiology, but primary hypogammaglobulinemia (associated with a primary immune deficiency) may include the following:

  • Growth retardation

  • Abnormalities of lymphoid tissue and organs (eg, a paucity of tonsillar tissue, adenoids, and peripheral lymph nodes)

  • Developmental abnormalities (eg, of skeleton or chest wall)

  • Abnormalities of skin and mucous membranes (eg, scars, rash, or livedo reticularis)

  • Ear, nose, and throat abnormalities (eg, tympanic membrane perforation, purulent nasal discharge, cobblestone pattern of pharyngeal mucosa, and nasal exudate)

  • Pulmonary abnormalities suggestive of recurrent infections (eg, bronchiectasis and lung fibrosis with rales, rhonchi, and wheezing)

  • Cardiovascular abnormalities associated with DiGeorge or CHARGE syndrome

Physical exam findings in secondary hypogammaglobulinemia will vary by etiology.

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies that may be helpful include the following:

  • Serum immunoglobulin levels (IgA, IgG, and IgM)

  • Complete blood count with differential

  • Antibody response for recall antigens

  • Isohemagglutinins (especially useful if patient already received IV or SC Ig)

  • Peripheral blood lymphocyte immunophenotyping

  • Evaluation of cellular immunity (cutaneous delayed-type hypersensitivity or mitogen and antigen proliferation)

Imaging studies that may be useful include the following:

  • Chest radiography

  • High-resolution computed tomography (HRCT) to evaluate for bronchiectasis

The following tests may be considered as circumstances warrant:

  • Microarray for DiGeorge (primarily T cell disorder, but T cell disorders will lead to B cell dysfunction if severe) and evaluation for genetic variaqnts of CVID if warranted

  • HIV testing (although untreated HIV is classically assciated with hypergammaglobulinemia, late-stage HIV may be assciated with loss of Immunoglobulin)

The following biopsy procedures may also be considered:

  • Lymph node biopsy (for rapidly enlarging lymph nodes to rule out infection or malignancy)

  • Thymus biopsy (indicated only for thymoma)

See Workup for more detail.

Management

In cases of slightly low immunoglobulin (IgG) where antibody production is intact, watchful waiting is encouraged. Infants with transient hypogammaglobulinemia often have resolution of this finding without intervention. Some individuals will have low immunoglobulin without disruption of ability to produce antibody, and require no intervention.

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

  • X-linked agammaglobulinemia (Bruton disease; XLA)

  • CVID

  • Severe combined immunodeficiency (SCID) prior to stem cell or bone marrow transplantation

  • Hyper-IgM

  • ADA deficiency

  • Wiskott-Aldrich syndrome (WAS)

  • Syndromes associated with low immunoglobulin or poor antibody production

  • Sometimes specific antibody deficiency

If poor T-cell function is also a part of the immune deficiency (ie, severe combined immune deficiency or combined immune deficiency), stem cell transplant or bone marrow transplant may be the definitive treatment, and may replace B cell function so that IgG replacement is no longer necessary[1, 2]

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

  • IVIG is not indicated for lymphoproliferative disorders unless immunoglobulin levels are low in association with recurrent infections or if IVIG is being used for autoimmune conditions that may accompany these disorders

  • If IgG is being lost through the gut or kidney, replacement of IgG will not be effective

See Treatment and Medication for more detail.

Background

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.

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

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.

 

Presentation

History

Most patients with hypogammaglobulinemia present with a history of recurrent infections, failure to thrive, autoimmune disease, and more rarely with malignancies (especially leukemias or lymphomas). A detailed clinical history should emphasize the following.

Family history

A family history of frequent infections, persons receiving immunoglobulin, or infants who died at an early age due to infection are all suggestive of immune deficiency.

A positive family history may suggest the diagnosis and guide testing for XLA, 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]  The same is true of other X-linked immune deficiencies.

A family history of an infant with severe combined immunodeficiency (SCID) should suggest prompt testing of subsequent infants (although, most infants with SCID are now detected by newborn screening).

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.

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, although this is controversial.

Rarely, patients with undetectable IgA antibodies may develop anti-IgA antibodies of the IgE isotype. Once sensitized, these patients may be at risk for anaphylactic reactions if they receive blood products containing 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.

In X-linked hyper-IgM syndrome, 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 and patients are at risk for bacterial infections, but fungal and protozoan infections are often responsible for more severe morbidity than bacterial infections since bacterial infections 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, and cytomegalovirus infections may occur.

Patients with XLA and with autosomal recessive forms of agammaglobulinemia 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 in this age of antibiotic availability is often delayed. XLA may occasionally 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 also found in hyper-IgM syndrome, but these patients can also be susceptible to P jeroveci infection and other opportunistic infections, which may represent the initial presentation of an immunodeficiency.

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

CVID leaves patients prone to the same infections that patients with agammaglobulinemia have with a variable defect in cell mediated immunity. CVID is not one disorder but a variety of defects, and 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.

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.

Non-infectious gastrointestinal symptoms

Malabsorptive enteritis occurs in up to 50% of patients with CVID.

Gastritis with achlorhydria and pernicious anemia may occur.

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

Immune cytopenias are the most common autoimmune manifestation of CVID

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.

Physical

See the list below:

  • Growth retardation: Early-onset recurrent infections and GI problems associated with immune deficiencies can cause growth retardation. However, the presence of normal growth does not rule out these disorders. Giardiasis and other GI problems may cause weight loss in adults.

  • Lymphoid tissue and organs

    • A paucity of tonsillar tissue, adenoids, and peripheral lymph nodes is seen in XLA and combined T-cell/B-cell deficiencies and should provide important clues to their diagnosis.[5]

    • Diffuse lymphoid hyperplasia may accompany CVID and some hyper-IgM syndromes, and splenomegaly with or without hypersplenism occurs in 25% of patients with CVID. Lymph node biopsy from patients with CVID may show the absence of follicles and germinal centers with a relative paucity of plasma cells, or reactive hyperplasia may be present. The stomach and/or intestines may have hypertrophic folds and/or lymphoid hyperplasia in CVID.

  • Developmental abnormalities: Skeletal and chest wall abnormalities affecting the vertebral bodies and the chondrocostal junctions occur in patients with adenosine deaminase deficiency.

  • Skin and mucous membranes

    • Severe eczematoid rash is typical of WAS.

    • Livedo reticularis with muscle weakness or a dermatomyositis-like syndrome may present with XLA.

    • A lupuslike rash may occur with CVID.

  • Ear, nose, and throat

    • Tympanic membrane perforation or scarring, with hearing loss, can occur because of recurrent otitis media. Purulent nasal discharge, a cobblestone pattern of pharyngeal mucosa, and nasal exudate usually are present, consistent with chronic sinusitis, which is one of the most common findings in these patients.

    • Note the presence or absence of tonsillar tissue.

  • Pulmonary

    • Recurrent bronchitis and pneumonias can lead to bronchiectasis and lung fibrosis.

    • Rales, rhonchi, and wheezing can be observed on lung examination in such patients.

    • Digital clubbing may result from chronic obstructive pulmonary disease (COPD).

  • Cardiovascular system

    • Chronic respiratory insufficiency can result in pulmonary hypertension and, eventually, right-sided heart failure.

  • Neurologic

    • Paralytic poliomyelitis may occur in patients with antibody deficiencies following vaccination with live attenuated poliovirus vaccine, although live polio vaccinations are no longer used in the United States.

    • Deep sensory loss with decreased vibratory and position sense of limb segments is seen in pernicious anemia.

Causes

Hypogammaglobulinemia may be caused by primary (congenital) or secondary (acquired) disorders.  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.

  • Primary or congenital B-cell disorders

    • X-linked agammaglobulinemia (XLA, Bruton agammaglobulinemia)

      • Mutations in the Bruton tyrosine kinase (BTK) gene and protein have been implicated in this entity.[1, 5]  

    • Autosomal recessive agammaglobulinemia (ARA)

      • Generally, the only differences between ARA and XLA, other than occurrence of the former in females, are the pattern of inheritance and the genes implicated. The clinical presentation, lab abnormalities, age at onset, and treatment of ARA are identical to those of XLA.

      • The implicated molecules or genes include IgM heavy chain, Ig alpha, surrogate light chain, B cell linker protein (BLNK), and leucine-rich repeat – containing 8 (LRRC8) in different patients.

    • Hyper-IgM syndromes (including deficiencies of CD40 ligand (CD154), activation-induced cytidine deaminase [AID], and uracil-nucleoside-glycosylase [UNG]): This is a heterogeneous group of disorders in which normal or elevated IgM levels are found along with low levels of IgA, IgG, and, sometimes, IgE. One X-linked form of hyper IgM is associated with CD40 ligand (CD154) defects and may have impaired T-cell function and associated opportunistic infections.[2]  

    • Isolated non-IgG immunoglobulin deficiencies (IgM, IgA)

      • IgA deficiency is defined as an absent IgA level with normal IgG and IgM levels in patients older than 4 years in whom other reasons for hypogammaglobulinemia have been ruled out.

      • No molecular or genetic basis for most cases of this disorder is known.

    • IgG subclass deficiency

      • This syndrome is defined as one or more IgG subclasses at 2 standard deviations below the mean, with normal total IgG and IgM levels. IgA levels may also be low.

      • Whether this entity should be categorized under the CVID heading is controversial. By definition, 2.3% of the "normal" population fits such a classification. A few case series report these patients having recurrent sinopulmonary infections and environmental allergies.

      • No specific genetic cause is identified

    • Specific antibody deficiency (SAD) or specific polysaccharide antibody deficiency (SPAD)

      • Though the prevalence of this condition is not known, it is occasionally found in patients with recurrent sinopulmonary infections. SAD is characterized by total levels of IgG, IgA, and IgM within the normal range, but with an inability to make appropriate quantities of specific antibodies and/or to retain memory of polysaccharide vaccines. As with most humoral immune deficiencies described, recurrent sinopulmonary infections are the hallmark.

      • No consensus exists as to the titer or number of pneumococcal serotype antibody responses that should be elicited in order to fit into this disorder.[7]

      • Age must be considered when entertaining this diagnosis. While no reliable age-adjusted criteria for polysaccharide response exists, the general guideline is that the younger the patient, the fewer the responses. The diagnosis should not be assigned to children younger than 2 years, because IgG2, IgA, and specific polysaccharide responses usually develop more slowly than other types of antibody response.

      • A positive response is usually defined as a titer to a specific serotype greater than 1.3 mg/mL or a 4-fold increase in preimmunization titers.[7] Some authors suggest that at least 3 serotypes showing specific antibody levels ≥2 µg/mL probably represents a normal antibody responsiveness, while others suggest that 9 out of 12 serotype responses is considered normal.

      • In patients who have already been vaccinated with conjugated pneumococcal vaccines, the actual response may be difficult to determine because prevaccination titers were not available to determine antibody increases, and no consensus exists about what values constitute protective titers in patients who only have postvaccination titers. Meningococcal and typhoid vaccines are other potential antigens that can be used to assess antibody responses.[8, 7] Antibody responses to polysaccharide antigens (eg, unconjugated pneumococcal polysaccharide vaccine) in normal children younger than 2 years are often poor, which is why protein conjugate vaccines are usually used in this age group.

    • Common variable immunodeficiency (CVID)

      • CVID is present in 1 in 5,000–7,000 people. CVID is so named because it is the most common primary immune deficiency.[3, 4] Variability, implied by the name, relates to the magnitude and classes of deficient serum immunoglobulins and also to the clinical course. CVID is usually differentiated from XLA and autosomal recessive agammaglobulinemia by the presence of B-cells, visible tonsils or a history of tonsillectomy, and palpable or even enlarged lymph nodes.

      • Individuals with CVID typically have recurrent upper and lower respiratory tract infections with encapsulated bacteria such as haemophilus, pneumococcus, staph, and meningococcus as well as and atypical bacterial pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Individuals with CVID also typically have recurrent sinusitis and bronchitis, and they frequently develop bronchiectasis, granulomatous lung disease, and lymphocytic interstitial pneumonitis. Gastrointestinal complications are also typical, including lymphonodular hyperplasia, inflammatory bowel disease, and nonspecific malabsorption. Enteric infections also occur; the most common are Campylobacter jejuni, Helicobacter pylori, and Giardia and hemolytic anemia.[4] One third of patients develop a lymphoproliferative disorder, including splenomegaly, generalized lymphadenopathy, or intestinal lymphoid hyperplasia. These patients are at 30- to 400-fold increased risk for developing non-Hodgkin lymphoma and other malignancies.[4]

      • This diagnosis should not be assigned to patients younger than 2 years, in whom hypogammaglobulinemia may represent a delay in the maturation of B-cell responses.

      • While no pathognomonic physical examination finding is typical, lymphadenopathy, splenomegaly, and/or hepatomegaly can all be present. Abnormal lung examination indicating bronchiectasis suggests long-standing disease. A patient could also have positive Hemoccult test results secondary to invasive bacterial infection.

      • Hallmarks of the disease are hypogammaglobulinemia and impaired specific antibody response to vaccination. Although patients with CVID classically have decreased levels of IgG, IgA, and IgM, some patients may have decreases in levels of only IgG, and some have elevated levels of IgM. Most patients with CVID have a normal number of B cells, but, in approximately one third of patients, the number of B cells with surface immunoglobulin is lower than normal. More detailed description of cellular abnormalities and related testing are described in the Medscape Reference article Pediatric Common Variable Immunodeficiency.

      • About 10 percent of patients have a family history of at least one relative with CVID or selective IgA deficiency, with autosomal dominant or recessive inheritance patterns. The remaining cases are believed to arise from sporadic mutations, although, in most cases, no such mutation has yet been identified. Defects in the molecules ICOS, TACI, and BAFF-R can apparently all result in phenotypes categorized as CVID, but the number of such mutations identified explains only a small percentage of CVID patients, and non-disease-causing polymorphisms are frequent.[9] The mainstays of treatment are regular IgG replacement (IVIG or SCIG) and, when indicated, antimicrobial therapy. However, many CVID patients require corticosteroids to control autoimmune manifestations, and splenectomy is not uncommon

    • Transient hypogammaglobulinemia of infancy

      • Transplacentally acquired maternal IgG is metabolized over several months (the half-life of immunoglobulins is 21 days) and usually falls below 0.3 to 0.4 g/L by 6 months of age. Normal infants begin making IgG shortly after birth; in some babies, this is delayed, but B-cells are present and IgG production eventually normalizes. Inadequate endogenous IgG production may remain in a prolonged deep trough at the nadir of the IgG levels, leaving the child susceptible to gastrointestinal infections, recurrent sinopulmonary infections, and frequent viral illnesses. In turn, these infections may present physiologic challenges to the vulnerable infant, further impairing the development of protective responses. Because of the rapidity of physiologic changes between ages 4 and 12 months, the trend across several IgG levels is likely a better prognostic indicator than any single level at one point in time.

      • IgG levels persistently below the 5th percentile for age is the sine qua non of this entity. Decreased levels of IgA are also common in this group, and low IgM levels may be seen, but less frequently. Most of these babies have normal lymphocyte counts for age and normal lymphocyte mitogen stimulation test results, and their IgG responses to initial protein vaccines such as DPT are frequently normal.

      • While no specific mechanism has been identified for this entity, its incidence is increased in families with other immunodeficiencies. This association suggests a genetic component

      • Generally, only prophylactic antibiotics are needed to protect these individuals. If IgG therapy is started because of intolerance or ineffectiveness of the antibiotics, it should be temporarily stopped every 3-6 months to re-assess endogenous production of immunoglobulins.

    • Immunodeficiency with thymoma (Good syndrome): Of patients with thymoma, 6-11% also have immunodeficiency, most commonly in the form of hypogammaglobulinemia. The concomitant occurrence of these conditions is termed Good syndrome. However, hypogammaglobulinemia often does not resolve with successful treatment/resection of the thymoma, and associated T-cell abnormalities may exist.

  • Combined T-cell and B-cell disorders

    • Severe combined immunodeficiency (SCID)

      • SCID, as its name implies, is the most severe of the pediatric immunodeficiencies. Suspicion of SCID is a truly emergent situation, as precipitous decline in clinical condition can occur with any infectious challenge. Neonates with SCID are usually indistinguishable from normal newborns, prompting a call for newborn screening so SCID can be detected before a potentially fatal infection occurs. Lymphopenia is characteristic of SCID, but age-specific norms must be used, since normal newborns should have higher lymphocyte counts than older children and adults.[1, 10]

      • On physical examination, absence of lymphoid tissue and undetectable thymus shadow on chest radiograph are typical. Erythroderma combined with lymphadenopathy and hepatosplenomegaly is typical of a SCID variant called Omenn syndrome.

      • In addition to age-adjusted lymphopenia, one or more reduced or absent lymphocyte populations and profoundly decreased T-cell mitogenic responses are also observed. An exception to this may occur if engraftment of maternal lymphocytes before birth has occurred, resulting in a form of graft versus host disease (GVHD). IgG levels are frequently normal within the first couple of months of life, since this is maternally derived.

      • SCID is a heterogeneous group of conditions caused by different mutations that interfere with development of T-cells, and, in some cases, B-cells and NK cells as well.[1] The most common mutations are in the cytokine receptor common gamma chain (in X-linked SCID); the common IL-2 and IL-7 receptor alpha chain; Janus tyrosine kinase-3 (JAK3); CD45; CD3 subunits gamma, delta, and epsilon; recombinase-activating gene proteins 1 and 2 (RAG-1, RAG-2); DNA cross-link repair protein 1C; adenosine deaminase; purine nucleoside phosphorylase; transporter 1 and 2, ATP-binding cassette (TAP1, TAP2); 4 components of major histocompatibility complex (MHC) class II gene transcription complex; and winged-helix nude transcription factor.

      • Hematopoietic stem cell (bone marrow) transplantation (HSCT) should be undertaken as early as possible and has been successful in up to 95% of cases in which it has been performed before 30 days of life.[1, 10] IgG replacement should be used, as well, and is usually continued for at least 12 months because B-cell engraftment and development after transplantation is usually delayed. These individuals should also be protected from exposure to infectious agents. Prophylaxis against P carinii is also recommended.

    • Wiskott-Aldrich syndrome

      • Classically, patients with Wiskott-Aldrich syndrome (WAS) present with eczema, petechiae, bruising or bleeding, recurrent severe infections (including opportunistic infections) autoimmune diseases, and B-cell lymphomas. X-linked inheritance is exhibited.[2]

      • Thrombocytopenia and small platelet size are usually seen on routine blood work results. Low levels of IgG, IgM, and IgE and, sometimes, elevated IgA levels, as well as impaired specific antibody production, are also seen. T-cell abnormalities are also seen, including lymphocytopenia and impaired T-cell function.

      • WAS protein mutations define this entity.

      • The only curative treatment is hematopoietic stem cell (bone marrow) transplantation. Prior to bone marrow transplantation, patients with WAS are treated with prophylactic antibiotics, splenectomy, and IVIG. While gene therapy remains unproven for WAS at this time, good clinical and laboratory results have been observed in a few patients.[11]

    • Ataxia-telangiectasia (A-T)

      • Patients with A-T develop gait ataxia, oculocutaneous telangiectasias, growth retardation, and immune deficiency. However, this diagnosis may not be apparent early because many of these signs and symptoms develop slowly with time and/or may present with regressive loss of developmental milestones, and thus may be difficult to recognize.

      • Clinical immunodeficiency is seen in infancy or early childhood. Growth retardation and delay in gross motor coordination are also seen. Oculocutaneous telangiectasias do not typically appear until patients are aged 3-5 years, so they are not useful in making an early diagnosis.

      • Mutations in the ATM gene and the protein it encodes, nibrin, are responsible for this disorder. The mutations result in defective DNA repair and increased susceptibility to ionizing radiation. Therefore, radiography should be minimized, and the risk of malignancy is very high.

      • IgA deficiency, IgG subclass deficiencies, impaired specific antibody response, and derangement in lymphocyte population are typical of A-T. Elevated levels of alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) are seen in 95% of patients with A-T and are virtually pathognomonic.

      • Antibiotic prophylaxis, as well as IgG replacement, is appropriate for the treatment of the immunodeficiency aspect of this syndrome. A multidisciplinary approach to the patient as a whole should be undertaken to address the multisystem nature of this disease.

  • Secondary or acquired diseases

    • Nephrotic syndrome: Decreased levels of IgG can appear with normal levels of IgA and IgM in the nephrotic syndrome.

    • Protein-losing enteropathy

      • Intestinal lymphangiectasia, which is sometimes considered as a subset of protein-losing enteropathies, frequently causes not only loss of protein, but also of B-cells, leading to lymphopenia. This occurs because of intestinal lymphatic blockade with resulting leakage of lymphatic fluid and cellular components into the lumen.

      • Both nephrotic syndrome and protein-losing enteropathies manifest with hypoalbuminemia and, usually, edema. IgG levels are affected more than IgM or IgA levels in protein-losing enteropathies. However, levels of IgG, IgM, and IgA, and the cells that produce them, may all be reduced in severe protein-losing enteropathy.Specific antibody response to vaccines is usually normal in these patients despite low levels of immunoglobulin particularly IgG and IgA.

    • Catabolic disorders: Increased catabolism occurs in various diseases, including the B-cell lineage malignancies, severe burns, and myotonic dystrophy.

    • Immunosuppressive therapy

      • Immunosuppressant medication can cause hypogammaglobulinemia, especially in the setting of solid organ transplantation. Long-term corticosteroid treatment can also result in hypogammaglobulinemia, which may, rarely, be symptomatic. Patients with asthma and with hypogammaglobulinemia secondary to corticosteroid use retain specific antibody responses and, thus, are not necessarily candidates for immunoglobulin replacement therapy. Patients presenting with sinusitis and/or bronchitis with secondary bronchospasm, however, may have CVID or other forms of antibody deficiency that will respond to IgG replacement. Patients who take daily doses of ≥12.5 mg prednisone for 1 year or more are more likely to have hypogammaglobulinemia.

      • Immunosuppressants combined with corticosteroids may create an even greater propensity toward hypogammaglobulinemia. Such treatments are commonly used in patients with autoimmune and neoplastic diseases. Rituximab (anti-CD20) treatment in neoplastic and/or autoimmune disease also may be associated with hypogammaglobulinemia. Chemotherapy, autologous stem cell transplantation, or both may contribute to the hypogammaglobulinemia.

      • Although malnutrition and radiation have been purported to cause secondary hypogammaglobulinemia, the literature supporting this association is weak. For example, studies on malnourished African children showed that cellular immunity was much more impaired than humoral immunity. Total lymphoid irradiation used in the past for rheumatoid arthritis did not decrease rheumatoid factor levels, suggesting that nonmyeloablative irradiation has little effect on immunoglobulin levels. Thyrotoxicosis is not associated with hypogammaglobulinemia.

    • Lymphoproliferative malignancies

      • Chronic lymphocytic leukemia: B-cell chronic lymphocytic leukemia (B-CLL) is often associated with hypogammaglobulinemia and infections.[12] Multiple myeloma and other monoclonal gammopathies may result in antibody deficiency in the face of apparently normal total IgG levels because of the contribution of the paraprotein to the total IgG level. Tumor cells provoke several alterations to normal regulatory T cells, which impair the correct maturation of B cells.

      • B-CLL cells also directly inhibit Ig-secreting plasma cells (PCs), which may account for the humoral immunodeficiency. This phenomenon is mediated by the interaction of CD95L molecules expressed by B-CLL cells with the death receptor CD95 that is up-regulated on the plasma cells of patients with CLL, leading to increased plasma cell apoptosis and, subsequently, to hypogammaglobulinemia. Treatment of CLL-associated hypogammaglobulinemia with IgG replacement may have only marginal benefit unless specific antibody deficiency has actually been demonstrated.[12]

    • Prematurity in infants: Babies born before completion of the third trimester in utero frequently lack adequate maternal immunoglobulin and may also have more rapid metabolism of what IgG they have received.

    • Drug-related: Anti-seizure medications such as phenytoin, carbamazepine, and lamotrigine may cause reversible hypogammaglobulinemia. Chlorpromazine, phenytoin, carbamazepine, valproic acid, D-penicillamine, sulfasalazine, and hydroxychloroquine have been implicated in IgA deficiency.

 

DDx

 

Workup

Laboratory Studies

Levels of serum immunoglobulin

The evaluation of patients with suspected hypogammaglobulinemia should include quantitative measurement of serum immunoglobulins. If these levels are normal and a humoral immunodeficiency still is suggested, antibody response to specific antigens (polysaccharide and protein antigens) should be determined.[13, 8, 7, 5] The impaired antibody responses to various pathogens in hypogammaglobulinemic states may make serological diagnosis of certain infections (eg, HIV, Epstein-Barr virus [EBV]) difficult. In these patients, nucleic acid detection methods (ie, PCR or reverse PCR) may be the best diagnostic tests for certain viral infections.

Perform serum protein electrophoresis for presumptive diagnosis of hypogammaglobulinemia or monoclonal protein. Quantitative methods using immunodiffusion or nephelometry are used for the precise measurements of each isotype of Ig. Enzyme-linked immunosorbent assay is used for IgE quantitation.

Values must be compared with age-standardized reference ranges.

Common variable immunodeficiency (CVID) is defined by IgG levels less than 2 standard deviations below the mean, with equally low levels of IgA, IgM, or both.[13, 10]

Serum IgA is less than 5 mg/dL, with normal IgG and IgM levels, in selective IgA deficiency. levels of IgG2 and IgG4 also may be decreased, especially in patients with sinopulmonary infections.

In hyper-IgM syndromes, IgM may be markedly increased to levels frequently higher than 1000 mg/dL. However, the level of IgM often gradually increases with time and may be normal in children. levels of IgG, IgA, IgE, and the lymphocytes bearing these antibodies are decreased. IgM response to antigens is possible, but IgG and IgA responses are absent or diminished.

Antibody response after immunization

Vaccination-associated antibodies to diphtheria, tetanus toxoid, and HIB are normally demonstrable in patients who have received these vaccines, reflecting memory B-cell responses. Neoantigen responses may better reflect a patient’s current ability to mount antibody responses.

Typically, immunization with unconjugated pneumococcal vaccine is used to assess the response to polysaccharides by comparison of pre- and post-immunization titers (generally, a 4-fold rise is considered adequate).[7] Vaccine-induced antibodies should be determined 4-8 weeks after pneumococcal immunization. Pneumococcal immunization should be repeated if the response is inadequate after the first immunization, and remaining titers should be determined 8-12 months later, if impaired immunologic memory is suspected.

Isohemagglutinins

IgM antibodies to A and/or B blood group antigens should be checked if the other tests results are normal and the patient is unable to mount a response to specific antigens. Antibodies to blood group antigens A or B would not be expected to be present if the patient's blood group is A or B respectively, or AB. These antibodies normally develop in the first year of life in response to ingestion of cross-reacting animal antigens in food.

The production of these antibodies is normal in protein-losing states, in contrast to extremely low levels in XLA.

Peripheral blood lymphocyte immunophenotyping

Peripheral B cell levels are variable.

Their number is normal in 75% of patients with CVID, but their surface phenotype may be immature.

T-lymphocyte number and function are intact in most cases of pure B-cell disorders.

Reversal of the ratio of helper (CD4) to suppressor (CD8) T cells has been reported in CVID, leading to nonreactive delayed-type hypersensitivity (DTH) test results. In combined T-cell and B-cell disorders, peripheral T cells are absent or decreased, with negative DTH test results.

Evaluation of cellular immunity

Cutaneous delayed-type hypersensitivity

Delayed-type hypersensitivity testing helps evaluate the memory response of cellular immunity to a previously encountered antigen. This test is not reliable in children younger than 1 year, and the response frequently is suppressed following viral and bacterial infections and during or after glucocorticoid therapy.

The test is read by measuring the induration 48-72 hours following administration of mumps skin test antigen or candidal antigen (at 1:100 wt/vol dilution; if no reaction, use 1:10 dilution), tuberculin (0.1 mL containing 2-10 IU of purified protein derivative), and trichophytin (1:30 wt/vol dilution). The test result is considered positive if the induration is greater than 5 mm (or >2 mm in children). Aqueous tetanus toxoid is no longer available for anergy panel testing.

Complete blood count (CBC)

The CBC may indicate lymphopenia or lymphocytosis, which may be seen with secondary causes of hypogammaglobulinemia (intestinal lymphangiectasia and chronic lymphocytic leukemia [CLL], respectively). The absolute lymphocyte count must be compared to age-specific norms because infants normally have higher counts than older children and adults. Immunophenotypic lymphocyte studies are useful in determining the most likely defect in infants with severe combined immunodeficiency (SCID) and may be required to diagnose CLL.

Renal studies

Renal disease in which protein loss causes hypogammaglobulinemia is easily diagnosed by quantitation of the total 24-hour urinary protein excretion.

Gastrointestinal studies

Protein-losing enteropathy that causes hypogammaglobulinemia may be more difficult to diagnose. Increased alpha1-antitrypsin (which is not present in normal diet) loss in the stool can be quantified in a 24-hour clearance procedure. Alternatively, a nuclear scan using technetium 99m dextran can be used to diagnose and localize protein-losing enteropathy.

Intestinal lymphangiectasia, which is sometimes considered a subset of protein-losing enteropathies, manifests not only with protein loss but also with lymphopenia. This occurs because of intestinal lymphatic blockade with resulting leakage of lymphatic fluid and cellular components into the lumen. Imaging and endoscopy are useful in diagnosing intestinal lymphangiectasia. However, this is often a "patchy lesion," and the diagnosis may be difficult.

Imaging Studies

Chest radiograph

In many patients with CVID and primary hypogammaglobulinemia, recurrent or chronic infections lead to abnormal findings on chest radiograph, such as interstitial infiltrates, bronchiectasis, emphysema or bullae, and scarring. Chest radiograph findings may be normal despite the presence of structural abnormalities. CVID patients often have hilar adenopathy and/or granulomata.[14]

Although chest radiograph is an appropriate follow-up test for these patients, some argue for the use of high-resolution computed tomography (HRCT) as the criterion standard.

The absence of a thymic shadow is a common finding in patients with SCID. Thymomas may be identified on chest radiograph in patients with Good syndrome.

Cupping and flaring of the costochondral junctions is typical for adenosine deaminase (ADA) deficiency.

High-resolution computed tomography (HRCT) and nuclear scanning

HRCT scans may uncover important lung abnormalities in patients with CVID and primary hypogammaglobulinemia.[15] These include, but are not limited to, pulmonary fibrosis, bronchiectasis, parenchymal scarring, pleural thickening, and, less commonly, emphysema or parenchymal nodules.

HRCT scans are more sensitive than chest radiograph for detecting asymptomatic structural changes of airways and lung parenchyma that sometimes occur despite appropriate intravenous immunoglobulin (IVIG) therapy.[15]

Imaging studies of the abdomen may show organomegaly. Splenomegaly may be observed in CVID in the absence of lymphoma or lymphoproliferative disease. Pathologic-appearing para-aortic and other abnormal abdominal lymph nodes may be stable findings in CVID; they should be monitored carefully and may require studies using other modalities (fluorodeoxyglucose positron emission tomography [FDG-PET] and/or biopsy) to rule out malignancy.

Other Tests

ADA levels should be measured in patients with SCID. The diagnosis of ADA deficiency is made by finding ADA levels less than 1% of the reference range. Cost-benefit analysis dictates that enzyme assays should be checked before genetic analysis. Also in the differential are mutations in purine nucleoside phosphorylase; this should be evaluated along with ADA levels. Tests can be done prenatally on amniotic fluid.

Absent or decreased Wiskott-Aldrich syndrome protein (WASP) can be determined by flow cytometry or western blotting. For Wiskott-Aldrich syndrome (WAS), sequence analysis determines 99% of mutations known to cause the disease entity.

Prenatal diagnosis of X-linked agammaglobulinemia (XLA), X-linked hyper-IgM syndrome (XHM), WAS, and ADA deficiency can be accomplished by restriction fragment length polymorphism (RFLP) using fetal blood, amniotic cells, or chorionic villus tissue.

The most consistent feature of individuals with XLA is the absence or extreme decrease in the number of B cells (CD19+ cells). The BTK gene contains the mutation.

Umbilical cord blood can be used in the prenatal diagnosis of some of these disorders. B cells are absent in XLA. T cells are absent in X-linked SCID. "Bald" lymphocytes found on scanning electron microscopy is diagnostic of WAS. Red blood cell ADA is decreased in fetuses with ADA deficiency.

Commercial laboratories are available for many of these tests. More information can be found at www.genetests.org.

Histologic Findings

Lymph node biopsy is not a necessary diagnostic test in these disorders and can be complicated by poor healing and infection. However, it should be considered for rapidly enlarging lymph nodes to rule out infection or malignancy.

Rectal biopsy in CVID and IgA deficiency may show plasma cell and lymphoid cell infiltrate in rectal tissue. The presence of G lamblia or cryptosporidia can be documented via intestinal biopsy, which may show findings similar to sprue.

Thymus biopsy is indicated only in the presence of thymoma.

In XLA, lymph node biopsy reveals underdeveloped or rudimentary germinal centers. The same finding also can be documented in the tonsils, Peyer patches, and appendix.

In CVID, lymphoid follicles in lymph nodes, spleen, and gut are characterized by hyperplastic B-cell areas.

The thymus in patients with X-linked SCID resembles fetal thymus and is characterized by lobules of undifferentiated epithelial cells and depleted T-cell areas and, occasionally, both T-cell and B-cell areas.

In ADA deficiency, remnants of Hassall bodies can be seen in the thymus.

 

Treatment

Approach Considerations

Six distinct phenotypes of primary immunodeficiencies (PI) disease for which immunoglobulin replacement is or may be indicated include: (1) agammaglobulinemia due to absence of B cells; (2) hypogammaglobulinemia with poor antibody function; (3) normal immunoglobulins with poor antibody function; (4) hypogammaglobulinemia with normal antibody function; (5) isolated IgG subclass deficiency with recurrent infections; and (6) recurrent infections due to a complex immune mechanism related to a genetically defined PI disease. Recommendations are based on evidence categories ranging from quasi-experimental studies (IIb) to expert opinion.The list of PI diseases to be treated with immunoglobulins is likely to change in the future with better diagnosis and characterization of the diseases.

The goals of immunoglobulin (Ig) replacement therapy (IgRT) for patients with primary immunodeficiency is to provide adequate replacement immunoglobulins to minimize potentially fatal infections and prevent complications associated with the disease and improve quality of life. A brief overview of benefits of IgRT is in some of the phenotype of PI diseases is provided.  

Agammaglobulinemia due to absence of B cells

Both the X-linked (Bruton agammaglobulinemia), accounting for 85% of cases, and autosomal recessive forms are associated with extremely low number or absence of B cells. Agammaglobulinemia is characterized by serum IgG levels of less than 100 mg/dl, IgM of less than 20 mg/dl, IgA of less than 10 mg/dl, and peripheral CD-19+ B cell of less than 2%. The principal manifestation is recurrent upper and lower respiratory tract infections. A continual IgRT is an absolute necessity and is life saving. Retrospective analyses of data from agammaglobulinemic children have revealed that the number and severity of infectious complications are inversely correlated with the dose of IVIG administered. Serious bacterial infections and enteroviral meningoencephalitis were prevented when the IgG trough levels were maintained above 800 mg/dl.

Other combined PIs in which the production of antibodies is or can be abnormal

In these disorders, B-cell function and or numbers can be impaired, leading to an inability to generate effective antibody responses. The disorders for which immunoglobulin is variably used fall into three categories: (1) Milder forms of combined immunodeficiencies (such as that caused by partially functional mutations in recombinase-activating genes [RAG]) and (2) Combined immunodeficiencies with associated or syndromic features (such as Wiskott-Aldrich syndrome).

Diseases of immunodysregulation (such as CD27 deficiency). In SCID, immunoglobulin replacement is also necessary in the post-transplantation period, during gene therapy or enzyme replacement (for adenosine deaminase deficiency), until B-cell function is restored.

Hypogammaglobulinemia with impaired specific antibody production

CVID is the prototype of this category. The other includes unspecified hypogammaglobulinemia and hyper-IgM or antibody class-switch deficiency both X-linked type (CD 40L) and autosomal recessive type (activation induced cytidine deaminase, CD40 deficiency). This group is characterized by decreased immunoglobulin concentration and inability to respond with IgG antibody on protein or polysaccharide antigen challenge. These patients are prone for bacterial sinopulmonary infections, chronic lung disease and dysfunction. In patients with CVID early and adequate IgRT has shown to decrease both acute and chronic lung infections and its sequelae.

Normal levels of immunoglobulins with impaired specific-antibody production (selective antibody deficiency)

These patients have normal IgG levels are not hypogammaglobulinemia but have functional disorder with deficient response to polysaccharide antigen with pneumococcal vaccination pose a diagnostic and management challenge. IgRT is considered in settings of recurrent and severe infections, failure of antibiotics treatment or prophylaxis as a first line of treatment, complications of infections or antibiotics, impaired quality of life due to recurrent infections. Many of these patients’ particularly young children may require IgRT for limited time due to spontaneous recovery of responses to polysaccharide vaccine.

Hypogammaglobulinemia with normal-quality antibody response

This group includes transient hypogammaglobulinemia of infancy (THI). In patients with THI the IgG levels are lower than age specific normal during infancy and early childhood with or without lower IgM, IgA levels but specific antibody response is preserved as well as an intact cellular immunity. The definitive diagnosis is made only after correction of the immunoglobulin levels. Antibiotics both for treatment and prophylaxis is the initial step and IgG administration is only considered with antibiotic failure or significant recurrent infections. Continued close monitoring for recovery and excluding other causes of hypogammaglobulinemia is important.

Secondary hypogammaglobulinemia

Secondary hypogammaglobulinemia due to increased IgG loss can occur in may conditions (as discussed earlier) including chylothorax, lymphaniectasia, or protein-losing enteropathy or medications like anti seizure, corticosteroids or rituximab do not warrant IgG administration. However, the FDA has approved use of IgRT in patients with chronic lymphocytic lymphoma (CLL) and recurrent serious bacterial infections, low IgG levels, and sub protective antibody levels after vaccination. Numerous studies have shown the benefit of decreasing documented infections but without survival benefits.

Medical Care

IgG replacement therapy is the treatment of choice for most primary immunodeficiency syndromes, including X-linked agammaglobulinemia (Bruton disease; XLA), common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), hyper-IgM, adenosine deaminase (ADA) deficiency, and Wiskott-Aldrich syndrome (WAS). IgG is usually routinely administered intravenously (IVIG) or subcutaneously (SCIG). IgG replacement is usually needed for at least 1 year after hematopoietic stem cell transplantation (HSCT) in patients with SCID.

Patients with IgG subclass deficiency should not be given IVIG unless they fail to produce antibodies to protein and polysaccharide antigens and they have significant morbidity due to infection that cannot be managed with antibiotics alone. In selective IgA deficiency, IVIG therapy is not indicated.

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. Because of 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 secondary 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 for the treatment of lymphoproliferative disorders, unless Ig levels are low in association with recurrent infections or if IVIG is being used for autoimmune conditions such as immune thrombocytopenic purpura (ITP) or immune hemolytic anemia, which may accompany these disorders.

Live vaccines (eg, bacille Calmette-Guérin, polio, measles, rubella, mumps) should not be given to patients with T-cell disorders, XLA, or other severe B-cell disorders or to the family members of such patients. In patients with IgA deficiency, live vaccines are not an absolute contraindication if given intramuscularly.

High doses of IVIG or intrathecal Ig may be beneficial in patients with XLA who have enteroviral meningoencephalitis.

HSCT is the treatment of choice for patients with SCID and, if a matched donor is available, for a patient with ADA deficiency.[1]

In patients with ADA deficiency who lack an HLA-identical sibling, enzyme replacement with polyethylene glycol-ADA (PEG-ADA) may be an effective alternative therapeutic agent.

Tumor necrosis factor (TNF) inhibitors have been used to treat granulomatous diseases in patients with CVID.

Gene therapy has been shown to be successful in reconstituting immune function in infants with X-linked SCID, but efficacy is less proven in older children and young adults.[16] Gene therapy for ADA deficiency is most effective when patients receive myeloablative chemotherapy and are withdrawn from PEG-ADA beforehand. Case series of ADA-deficient patients receiving gene therapy have shown excellent results at 4-year follow-up.[17]

Timely vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is a key component to prevention of B-cell disorders, with changes implemented in the order and interval period of PCV13 and PPSV23 administration. The Advisory Committee on Immunization Practices (ACIP) has recommended routine administration of a dose of PCV13 followed at least 12 months later by a dose of PPSV23 for immunocompetent adults aged 65 years or older. For adults aged 65 years or older with immuncompromising conditions, functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants, ACIP has recommended an interval of at least 8 weeks between PCV13 and PPSV23 adminisration. ACIP also has recommended that all adults aged 65 years or older who already received PPSV23 should receive a dose of PCV13 at least 1 year after receiving PPSV23.[18]

Activity

Special restrictions on physical activity are not needed.

 

Medication

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.[19, 13, 20] 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.[19, 20]

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.[19] IVIG is approved for only two 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.[19]

A safe, effective administration of IgRT requires detailed attention to the selection of patient, patient preferences, product, administration facilities, and health insurance. It is best delivered by an expert in the field who is knowledgeable of diagnosis, treatment, and complexities. The AAAAI and primary immunodeficiency subcommittee has formulated eight guiding principles for successful IgRT therapy.

Dosing

IVIG

An acceptable starting dose is 400–600mg/kg every 3–4 weeks.[19, 20] After the fifth infusion, a steady state will be achieved. Annual trough levels measurement is enough. Dose or dosing interval needs to be adjusted to achieve optimal goals. Studies support individualizing the IgRT dose, dosing interval, and trough levels rather than a standardized dose in all patients to attain infection-free outcomes. It is best left to the discretion of the treating physician.

SCIG

Usual starting dose is 100–200 mg/kg of body weight each week. The dosing interval is flexible and can be given daily, weekly, biweekly, or monthly. The monthly dosing is only possible with addition of recombinant human hyaluronidase. Infusion rates generally range from 10 to 35 ml/hour/site with an infusion pump with volume of 15–40 ml per site. A 20% SCIG formulation allows lower volume and rate used per manufacturer’s guidelines. Typical sites are lower abdomen, outer thigh, upper arm, and buttock. A steady state can be monitored after 3 months.

Comparison of IVIG and SCIG (Open Table in a new window)

IVIG

SCIG

Advantages

 

Dosing — large dose

Intermittent and infrequent intervals

High levels of IgG

No venous access

Self infusion

Small volume

Steady state levels of IgG — less "wear-off’ effects

Compatible with working lifestyle

Home treatment — convenient

Less expensive

Rare IgA reactions

Disadvantages

 

Needs venous access

Trained personnel and healthcare facilities for administration

Large fluctuations — "wear-off" effects

More adverse effects

May not suit a busy working lifestyle

More frequent dosing and injections

Smaller volume/dose and multiple infusion sites

Needs education

Nonadherence issues likely

Some practitioners target trough levels 300 mg/dL higher than pretreatment levels, and trough levels >800 mg/dL may improve pulmonary outcomes. Some centers advocate a loading dose of 1 g/kg if the patient is agammaglobulinemic.[19, 13, 20]

Gammaglobulin may also be given intramuscularly or subcutaneously.[20] 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.

Vaccines

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.

Pneumococcal vaccine polyvalent (Pneumovax 23)

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

Pneumococcal vaccine 13-valent (Prevnar 13)

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.

Blood Product Derivatives

Class Summary

There are many FDA approved IgG preparations available in market with distinct features. The products used in the United States are derived from the plasma of screened donors in the United States The product undergoes several specific treatments to inactivate or remove blood borne pathogens that could be present. The preparations contain highly purified (generally >95 percent) polyvalent IgG. However, there are slight differences in the manufacturing procedures used by different producers, and different stabilizers (eg, sucrose, glucose, maltose or amino acids) used in the excipients making them unique and warrant precaution during substitution of immunoglobulin during treatment. Products also differ in storage requirements and shelf life. It is important for physician to familiarize and select appropriate product for his/her patient. Some of the products are listed below.2

FDA approved Immunoglobulin products available in US 2

A. Intravenous use (IV)

-Liquid-Bivigam 10%, Flebogamma DIF (5%, 10%), Gammaplex 5%, Octagam liquid (5%, 10%), Privigen 10%

-Lyophilized-Gammagard S/D 5%, Carimune NF 5%         

B. Intravenous and Subcutaneous use (SC)

-Liquid-Gammagard 10%, Gammaked 10%, Gamunex 10%

C. Subcutaneous use (SC)

                -Liquid-Cuvitru 20%, Hizentra 20%

                -Liquid with hyaluronidase-Hyqvia 10%

Immune globulin IV (IGIV; Bivigam, Flebogamma DIF, Gammaplex, Octagam, Privigen, Gammagard S/D, Carimune NF)

Immune globulins may work via several mechanisms, including the blockage of macrophage receptors, the inhibition of antibody production, the inhibition of complement binding, and the neutralization of pathologic antibodies.

Immune globulin SC (Gammaked, Gamunex, Cuvitru, Hizentra, Hyqvia)

Immune globulins neutralize circulating myelin antibodies through anti-idiotypic antibodies; downregulates proinflammatory cytokines, including interferon gamma; block Fc receptors on macrophages; suppress inducer T and B cells while augmenting suppressor T cells; block the complement cascade; promote remyelination; and may increase immunoglobulin G (IgG) in cerebrospinal fluid (10% of cases).

 

Follow-up

Further Outpatient Care

See the list below:

  • Regular follow-up of the following parameters is necessary:

    • Growth and development should be monitored in children.

    • Chest radiograph and, if pulmonary abnormalities are suggested, high-resolution CT (HRCT) should be performed and repeated annually or as appropriate.

    • Pulmonary function tests should be performed and, if abnormal, monitored annually.

    • Immunoglobulin trough levels greater than or equal to 500 mg/dL are considered satisfactory, but levels greater than 600 mg/dL may be beneficial in patients with chronic lung or sinus disease. Doses and treatment intervals should be titrated in individual patients to determine the level needed to prevent recurrent infection without excessive use of this expensive medication.

    • Liver function tests should be performed and, if abnormalities are identified, nucleic acid tests should be used to determine if a potentially blood-borne infection (such as viral hepatitis) is present. Repeated results that suggest biliary disease may require follow-up with imaging studies of the liver and/or biliary tree to rule out malignancies or sclerosing cholangitis (the latter is seen in X-linked hyper-IgM syndrome [XHM]).

    • Lymphocyte surface marker analysis and serum immunoelectrophoresis may be indicated at routine intervals to screen for lymphoma and other malignancies.

Inpatient & Outpatient Medications

See the list below:

  • In most cases, intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) therapy can be given at home once safety has been established in the office/clinic. Home care nursing is usually required for IVIG therapy but may be unnecessary with SCIG.

  • Prophylactic and/or rotating full-treatment dose antibiotics may be useful in patients with chronic otitis, sinusitis, or chronic/recurrent bronchitis with bronchiectasis.

  • Bronchodilators, inhaled corticosteroids, inhaled anticholinergics, or a combination thereof may be indicated for patients whose lung disease includes components of bronchospasm, or bronchorrhea.

Transfer

See the list below:

  • Personnel at centers specializing in the diagnosis and treatment of these patients should be consulted for initial evaluation and treatment.

Deterrence/Prevention

See the list below:

  • Liberal use of antibiotics helps decrease the frequency of infections. Certain experts use a rotating regimen of antibiotics on a monthly basis.

Complications

See the list below:

  • Spruelike syndrome with malabsorption is observed in 10% of patients with common variable immunodeficiency (CVID). Upon small bowel biopsy, this syndrome resembles gluten-sensitive enteropathy, except for the absence of plasma cells. Infectious enteritis can be mistaken for ulcerative colitis or Crohn disease; both seem to occur with increased frequency in patients with CVID. Children with CVID frequently have lymphoid hyperplasia in the intestines, which may be comprised of plasmacytoid cells of B-cell lineage.

  • Vaccine-associated poliomyelitis may occur in patients with X-linked agammaglobulinemia (XLA) who receive the attenuated live poliovirus vaccine (no longer commonly used for infants in the United States).

  • Persistent enteroviral infection and chronic sinusitis remain the major complications of patients with XLA.

  • Viral encephalitis caused by, in decreasing order, enterovirus, coxsackievirus, measles, and papovavirus are potentially rare and devastating complications of hypogammaglobulinemia.

  • Hearing loss due to chronic otitis media or meningoencephalitis may affect as many as one third of patients with XLA and may also affect patients with CVID and specific antibody deficiency syndromes.

  • Bronchiectasis and cor pulmonale may complicate chronic or recurrent lower respiratory infections.

  • Autoimmune diseases[4]

    • The most common disorders are Coombs-positive hemolytic anemia and idiopathic thrombocytopenic purpura.

    • Neutropenia is observed less frequently. Nonimmune neutropenia is seen in young boys with XLA, and drug-induced neutropenia should be considered in other patients.

    • Pernicious anemia (due to autoimmunity) occurs in 10% of patients with CVID and is characterized by a younger age of onset and an absence of detectable antiparietal cell antibodies. Vitamin B12 deficiency should be considered in patients with CVID who do not have evidence of blood loss or iron deficiency.

    • Other less common autoimmune disorders have been reported, including thyroid diseases, Addison disease, diabetes mellitus, biliary cirrhosis, alopecia totalis, rheumatoid arthritis, systemic lupus erythematosus, polymyositis, sicca syndrome, and Guillain-Barré syndrome.

  • The risk of cancer in patients with CVID is 5 times higher than in matched controls. A 47-fold increase in gastric cancer and a 30-fold increase in lymphoma have been reported. The role of chronic infection with Helicobacter and other enteric pathogens in these cancers is suspected. Benign lymphoproliferative disorders are much more common, affecting up to 30% of patients, and manifest as splenomegaly, with or without diffuse lymphadenopathy. They are distinguished from lymphomas by the presence of a mixture of B and T lymphocytes and by the absence of clonal B-cell and T-cell receptor rearrangement.

  • A noncaseating granulomatous disease involving the lungs, lymph nodes, skin, bone marrow, and liver has been described in patients with CVID.[14] This entity should be differentiated from mycobacterial and fungal infections. In the small subset of patients with aggressive disease, corticosteroids and tumor necrosis factor (TNF) inhibitors are the treatments of choice. Granulomatous disease in the lungs is often associated with hilar, retroperitoneal, or abdominal lymphadenopathy.

  • Anaphylactic reactions can occur in rare instances when patients with IgA deficiency receive blood products containing IgA.

  • The risk of graft versus host disease (GVHD) is high in patients with SCID because of their inability to reject foreign antigens. Infants with SCID may present with GVHD before transplantation, due to engraftment with maternal lymphocytes before birth.

  • A dermatomyositis-like syndrome, a rare complication of Bruton disease, is a constellation of edema of subcutaneous tissue, rash, and muscle weakness. Chronic enteroviral meningoencephalitis also can be observed with this disorder.

  • Complications related to immunoglobulin therapy[20]

    • Nonanaphylactic reactions: The most common adverse reactions to IVIG are back and abdominal pain, nausea, vomiting, chills, fever, and myalgias. The infusion should be discontinued until the symptoms subside; then, it should be restarted at a slower rate after administration of premedication (eg, oral or intravenous hydration, antipyretics, antiemetics)

    • Local reactions to SCIG are common but are rarely persistent or serious.

    • Anaphylactic reactions: These are rare. They are IgE-mediated in patients with IgA deficiency and occur from seconds to hours after the infusion is started. IgG anti-IgA antibodies may be responsible for anaphylactoid reactions due to complement activation. Typical symptoms consist of flushing, facial swelling, dyspnea, and hypotension. The infusion should be stopped, and the patient should receive epinephrine, glucocorticoids, and antihistamines. Pure cutaneous reactions such as flushing and urticaria can be treated as nonanaphylactic reactions, with supportive and symptomatic therapy as needed.

Prognosis

See the list below:

  • Prognosis has improved significantly since the introduction of IVIG therapy to routine practice.

    • Mortality due to overwhelming infections remains a major risk for these patients, 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.

    • For those who survive long enough, autoimmune diseases and cancers become a serious threat because the incidence of these diseases is several-fold higher in these patients than in matched controls.[4]

    • SCID is a true pediatric emergency that may not be apparent on the newborn physical examination.[1] Patients do not survive beyond childhood unless a definitive treatment is performed. However, if hematopoietic stem cell transplantation is performed a bone within the first 3 months of life, the chance of survival is approximately 93%.

Patient Education

See the list below:

  • Despite aggressive IVIG therapy, these patients still have a higher incidence of infections compared to the general population.

  • Patients should be educated about the first symptoms of infection and the risk of overwhelming infections if they do not seek immediate medical attention.

  • Oral antibiotics covering encapsulated bacteria (eg, amoxicillin with or without clavulanic acid) should be made available for these patients at home for immediate use should they start experiencing symptoms of infection.

 

Questions & Answers

Overview

How is hypogammaglobulinemia characterized?

What are the signs and symptoms of hypogammaglobulinemia?

Which physical findings are characteristic of primary hypogammaglobulinemia?

What lab tests are performed in the workup of hypogammaglobulinemia?

Which imaging studies are performed in the workup of hypogammaglobulinemia?

Which lab tests may be considered in the workup of hypogammaglobulinemia?

When is biopsy indicated in the workup of hypogammaglobulinemia?

When is watchful waiting indicated in the treatment of hypogammaglobulinemia?

When is replacement IgG indicated in the treatment of hypogammaglobulinemia?

When is IgG replacement indicated in the treatment of secondary hypogammaglobulinemia?

What is hypogammaglobulinemia?

What is the pathophysiology of hypogammaglobulinemia?

What is the prevalence of hypogammaglobulinemia?

What is the mortality and morbidity associated with hypogammaglobulinemia?

Which patient groups have the highest prevalence of hypogammaglobulinemia?

Presentation

Which clinical history findings are characteristic of hypogammaglobulinemia?

Which family history findings are characteristic of hypogammaglobulinemia?

What is the typical age of onset for hypogammaglobulinemia?

Which microorganisms are associated with hypogammaglobulinemia?

What is the role of blood product reactions in the etiology of hypogammaglobulinemia?

Which recurrent infection history findings are characteristic of hypogammaglobulinemia?

What are the noninfectious GI signs and symptoms of hypogammaglobulinemia?

What are the musculoskeletal signs and symptoms of hypogammaglobulinemia?

Which autoimmune and collagen vascular diseases are associated with hypogammaglobulinemia?

Which growth findings are characteristic of hypogammaglobulinemia?

Which lymphoid tissue and organ findings are characteristic of hypogammaglobulinemia?

Which developmental abnormalities are characteristic of hypogammaglobulinemia?

Which skin and mucous membrane findings are characteristic of hypogammaglobulinemia?

Which ENT findings are characteristic of hypogammaglobulinemia?

Which pulmonary findings are characteristic of hypogammaglobulinemia?

Which cardiovascular findings are characteristic of hypogammaglobulinemia?

Which neurologic findings are characteristic of hypogammaglobulinemia?

What causes hypogammaglobulinemia?

Which genetic B-cell disorders cause hypogammaglobulinemia?

What are isolated non-IgG immunoglobulin deficiencies associated with hypogammaglobulinemia?

What is IgG subclass deficiency associated with hypogammaglobulinemia?

What is specific antibody deficiency (SAD) or specific polysaccharide antibody deficiency (SPAD) associated with hypogammaglobulinemia?

What is common variable immunodeficiency (CVID) associated with hypogammaglobulinemia?

What causes transient hypogammaglobulinemia of infancy?

What is immunodeficiency with thymoma (Good syndrome) associated with hypogammaglobulinemia?

What is SCID associated with hypogammaglobulinemia?

What is Wiskott-Aldrich syndrome associated with hypogammaglobulinemia?

What is ataxia-telangiectasia (A-T) associated with hypogammaglobulinemia?

What is nephrotic syndrome associated with hypogammaglobulinemia?

What is protein-losing enteropathy associated with hypogammaglobulinemia?

Which catabolic disorders cause hypogammaglobulinemia?

What is the role of immunosuppressive therapy in the etiology of hypogammaglobulinemia?

Which lymphoproliferative malignancies cause hypogammaglobulinemia?

What is the role of prematurity in the etiology of hypogammaglobulinemia?

What are the drug-related causes of hypogammaglobulinemia?

DDX

What are the differential diagnoses for Hypogammaglobulinemia?

Workup

What is the role of serum immunoglobulin measurement in the workup of hypogammaglobulinemia?

What is the role of antibody response after immunization in the workup of hypogammaglobulinemia?

What is the role of isohemagglutinins testing in the workup of hypogammaglobulinemia?

What is the role of peripheral blood lymphocyte immunophenotyping in the workup of hypogammaglobulinemia?

What is the role of delayed-type hypersensitivity testing the workup of hypogammaglobulinemia?

What is the role of a CBC panel in the workup of hypogammaglobulinemia?

What is the role of renal studies in the workup of hypogammaglobulinemia?

What is the role of GI studies in the workup of hypogammaglobulinemia?

What is the role of chest radiography in the workup of hypogammaglobulinemia?

What is the role of HRCT in the workup of hypogammaglobulinemia?

How is ADA deficiency diagnosed in hypogammaglobulinemia?

How is Wiskott-Aldrich syndrome diagnosed in hypogammaglobulinemia?

What is the role of prenatal testing in the workup of hypogammaglobulinemia?

Which histologic findings are characteristic of the workup of hypogammaglobulinemia?

Treatment

How is hypogammaglobulinemia treated?

How is agammaglobulinemia due to absence of B cells treated?

How is hypogammaglobulinemia in primary immunodeficiencies treated?

How is hypogammaglobulinemia with impaired specific antibody production treated?

How is hypogammaglobulinemia with selective antibody deficiency treated?

How is hypogammaglobulinemia with normal-quality antibody response treated?

How is secondary hypogammaglobulinemia treated?

What is the role of IgG replacement therapy in the treatment of primary hypogammaglobulinemia syndromes?

What is the focus of treatment for secondary hypogammaglobulinemia?

What is the role of live vaccines in the treatment of hypogammaglobulinemia?

What is the role of high dose IVIG in the treatment of hypogammaglobulinemia?

How is ADA deficiency treated in hypogammaglobulinemia?

What is the role of TNF in the treatment of hypogammaglobulinemia?

What is the role of gene therapy in the treatment of hypogammaglobulinemia?

What is the role of PCV13 and PPSV23 vaccines in the treatment of hypogammaglobulinemia?

Which activity modifications are used in the treatment of hypogammaglobulinemia?

Medications

What is the role of medications in the treatment of hypogammaglobulinemia?

Which medications in the drug class Blood Product Derivatives are used in the treatment of Hypogammaglobulinemia?

Which medications in the drug class Vaccines are used in the treatment of Hypogammaglobulinemia?

Follow-up

What is included in long-term monitoring of hypogammaglobulinemia?

Which medications are used in the treatment of hypogammaglobulinemia?

Which specialist consultations are beneficial to patients with hypogammaglobulinemia?

What is the role of antibiotics in the management of hypogammaglobulinemia?

What are the possible complications of hypogammaglobulinemia?

What is the prognosis of hypogammaglobulinemia?

What is included in the patient education about hypogammaglobulinemia?