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Synonyms and related keywords: hypogammaglobulinemia, B-cell disorders, T-cell disorders, humoral immunity deficiency, cellular immunity deficiency, antibody deficiency, immunoglobulins, Igs, common variable immunodeficiency, CVID, Bruton's disease, Bruton disease, intravenous immunoglobulin, IVIG, immunodeficiency, X-linked severe combined immunodeficiency, XSCID

Background

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

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

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

Pathophysiology

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

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

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

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

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

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

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

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

Frequency

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

Mortality/Morbidity

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

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

Race

No racial or ethnic predilection is recognized.

Sex

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

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

Age

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

History

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

Age of onset: Onset during childhood suggests an inherited disorder. Acquired hypogammaglobulinemias may start at any age, depending on the underlying cause (see Age).

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

Type of microorganisms: Knowing the type of microorganisms involved is helpful. Antibody deficiency and complement deficiency are associated with recurrent infections with encapsulated bacteria. Giardia lamblia infection is observed most often in patients with CVID or IgA deficiency. Opportunistic infections with viral and fungal pathogens suggest T-cell deficiency.

Blood product reactions: History of anaphylaxis following transfusion of blood products or vaccination may indicate an underlying immunodeficiency, particularly IgA deficiency. Patients with undetectable IgA antibodies may develop anti-IgA antibodies from the IgE isotype after receiving blood products. Once sensitized, these patients are at risk for anaphylactic reactions if they receive blood products containing even small amounts of IgA. Most patients who have anaphylactic reactions to blood transfusions, however, do not have IgA deficiency.

Family history: Obtaining a thorough family history is crucial in the evaluation of inherited disorders. Autoimmune disorders may be present in family members of patients with some of these disorders (eg, CVID, IgA deficiency).

• 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 play an important role in respiratory infections.
  • IgG2 is responsible for antibody responses to polysaccharides. Thus, isolated IgG2 deficiency or global IgG deficiency may be associated with recurrent upper and lower respiratory tract infections with encapsulated bacteria. Isolated IgG3 deficiency may be associated with recurrent sinopulmonary infections with viral infections and Moraxella catarrhalis.
  • In pure B-cell disorders, cellular immunity generally is intact and the frequency of viral, fungal, and mycobacterial infections is not increased.
  • In combined B-cell and T-cell disorders, both components of the immune response are defective, leading to mixed presentation with 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 are typically infected with pneumococcal, streptococcal, or staphylococcal organisms and H influenzae. While the upper respiratory system, conjunctiva, 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 aged less than 5 years. The typical invasive bacteria, as seen in XLA, are found in hyper IgM syndrome as well. These patients can also be susceptible to P carinii infection. This infection may be the first clue that the child has an immune deficiency. These patients usually exhibit increased susceptibility when aged less than 5 years.
  • Although most patients with IgA deficiency are healthy, some patients develop symptoms later in life after an uneventful childhood and early adulthood. Recurrent or chronic upper and lower respiratory tract infections leading to bronchiectasis or cor pulmonale are not common.
  • Although cellular immunity generally is intact in common variable immunodeficiency (CVID), occasional cases of severe abnormalities of cell-mediated immunity have been reported. In these cases, infections with fungi, mycobacteria, and P carinii may be seen, and severe and prolonged primary varicella or herpes zoster, herpes simplex, and cytomegalovirus infections have been reported.
  • Recurrent and life-threatening infections with encapsulated bacteria, particularly pneumococcal and meningococcal infections, characterize the rare hypo-IgM disorder (IgM deficiency).
  • During the first years of their lives, patients with transient hypogammaglobulinemia of infancy may have a high incidence of recurrent upper respiratory infections but do not usually have pneumonia or life-threatening infections.
  • Half the patients with Good syndrome (immunodeficiency with thymoma) have cell-mediated immunodeficiency and may present with mucocutaneous candidiasis, cytomegalovirus, or herpes zoster infection or P carinii.
    
• Gastrointestinal symptoms
• • Diarrhea with malabsorption syndrome is reported in more than 50% of patients.
  • Gastritis with achlorhydria and pernicious anemia may occur.
  • G lamblia and Campylobacter species are the pathogens involved in the gastrointestinal manifestations in many of these patients.
  • Other gastrointestinal diseases, such as sprue-like syndrome, ulcerative colitis, and Crohn disease, have been reported in CVID and IgA deficiency.
• 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, the arthritis is caused by a direct bacterial infection, ie, septic arthritis.
• Autoimmune and collagen vascular diseases
• • The incidence of autoimmune and collagen vascular diseases is increased, especially in IgA deficiency. Rheumatoid arthritis, systemic lupus erythematosus without renal disease, autoimmune hepatitis, neutropenia, hemolytic anemia, and endocrinopathies have been described.
  • Pure red cell aplasia, agranulocytosis, and myasthenia gravis have been reported with Good syndrome.

• Reactions to blood products: IgE-mediated anaphylactic reactions to the IgA contained in blood products may occur in patients with IgA deficiency. The most intriguing aspect of this problem is that the presence of the antibodies is not predictive of such reactions. In addition, patient's IgG anti-IgA may form immune complexes with infused IgA. These immune complexes then activate complement and can initiate anaphylactoid reactions due to mast cell activation by C3a and C5a.

Physical

• Growth retardation: Early-onset recurrent infections can cause growth retardation. However, the presence of normal growth does not rule out these disorders.
• Lymphoid tissue and organs
• • Paucity of tonsils, adenoids, and peripheral lymph nodes is seen in XLA and combined T-cell/B-cell deficiencies.
  • Diffuse lymphoid hyperplasia occurs in 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 shows the absence of follicles and germinal centers with occasional plasma cells.
• 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
• • Permanent scars can occur following skin infections.
  • Livedo reticularis with muscle weakness or a dermatomyositislike syndrome may present with XLA.
  • A lupuslike rash may occur.
• Ear, nose, and throat
• • Tympanic membrane scarring 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 lead to bronchiectasis and lung fibrosis, with their corollary of chronic respiratory insufficiency.
  • Rales, rhonchi, and wheezing are common findings on lung examination.
  • Digital clubbing may result from chronic obstructive pulmonary disease.
• Cardiovascular system
• • Chronic respiratory insufficiency results in pulmonary hypertension and, eventually, right-sided heart failure.
  • Signs such as a loud pulmonic heart sound, right ventricular heave, and tricuspid regurgitation murmur support the diagnosis of pulmonary hypertension.
  • Jugular venous distension, tender hepatomegaly, and lower-extremity edema suggest cor pulmonale.
• Neurologic
• • Paralytic poliomyelitis may occur in patients with antibody deficiencies following vaccination with live virus vaccines.
  • Deep sensory loss with decreased vibratory and position sense of limb segments are seen in pernicious anemia.

Causes

Hypogammaglobulinemia may be caused by primary (congenital) or secondary (acquired) disorders. The following lists of key disorders are not meant to be exhaustive.

• Primary or congenital B-cell disorders
• • X-linked agammaglobulinemia (Bruton disease)
  • • Patients with XLA have recurrent bacterial infections, including otitis media, sinusitis, and pneumonia. Approximately 85% of patients with agammaglobulinemia have XLA. The most common organisms isolated are H influenzae B (HIB) and S pneumoniae. A particular infection that is characteristic of XLA is enterocytopathogenic human orphan (ECHO) virus. Other clinical entities observed are P carinii pneumonia, vaccine strain poliovirus, and U urealyticum arthritis and bacteremia. 
    • Family history suggestive of x-linked lineage is typical, though sporadic cases are frequent. Bronchiectasis and gastroenteritis can occur over time with this ailment despite aggressive treatment. Small or absent tonsils and peripheral lymph nodes are the only consistent findings on physical examination.
    • Lab findings include IgG level less than 2 g/L, IgM and IgA levels less than 0.2 g/L, and peripheral CD19+ B cell counts (a marker characteristic of B cells in a particular stage of development) less than 2%.
    • This entity is usually identified within the first 2 years of life but may be first detected as late as age 5. 
    • Bruton tyrosine kinase (BTK) gene and protein have been implicated in this entity. Different mutations confer variable severity of illness, and direct sequencing is sometimes required for definitive diagnosis. The treatment includes regular IVIG infusions and antimicrobial therapy.
  • Autosomal recessive agammaglobulinemia (ARA)
  • • Generally, the only differences between ARA and XLA 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 activation-induced cytidine deaminase [AID] and uracil-nucleoside-glycosylase [UNG] deficiencies)
  • This entity 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 a CD40 ligand defect and may have impaired T-cell function and associated opportunistic infections. Patients afflicted with hyper IgM syndromes are prone to frequent bacterial sinopulmonary infections, gastrointestinal infections, and some forms of lymphoid hyperplasia.
  • • Along with the findings that comprise the name of this immune deficiency, tetanus-specific IgG is absent. T-cell function, as exhibited by mitogen response, is normal except in the CD 40 ligand (CD 40L) form. AID and UNG deficiencies both result in the hyper IgM phenotype. These molecules are involved in class switching and somatic hypermutation in B cells.
    • Regular treatment with IVIG is effective at reducing infectious sequelae in these patients.
  • Isolated non-IgG immunoglobulin deficiencies (IgM, IgA)
  • • IgA deficiency is defined as an absent IgA level with normal IgG and IgM levels in patients aged more than 4 years in whom other reasons for hypogammaglobulinemia have been ruled out. Most affected individuals are asymptomatic, but up to one third of patients develop respiratory and gastrointestinal tract infections, atopy and asthma, autoimmune disease, and malignancy. Severe infections, including septicemia and meningitis, are typically not seen with this entity.
    • Because some healthy children take a longer time to develop endogenous IgA, the case definition of IgA deficiency includes an age requirement of more than 4 years. Absence of IgA is the hallmark. Poor response to pneumococcal polysaccharide vaccines, as well as low levels of IgG2, IgG3, and IgG4, can also be seen with IgA deficiency.
    • No molecular or genetic basis for this disorder is known.
    • Treatment is usually not necessary. However, if antibiotic therapy is not successful, IVIG may be considered, though this treatment is controversial.
  • 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 discussed in the literature. Controversy does not end there. By definition, 2.3% of the population fits such a classification. That being said, these patients have recurrent sinopulmonary infections and tend to have environmental allergies, as well. A subclass deficiency is also seen in other immune-modifying illnesses, such as human immunodeficiency virus (HIV), ataxia telangiectasia, and Wiskott-Aldrich syndrome (WAS).
    • In addition to the criteria noted above, the response of these patients to immunization with polysaccharide antigen is poor or absent. This inability to mount a response may be seen in more in children. Evidence for IVIG efficacy is limited as treatment for this disorder; thus, prophylactic antibiotics and treatment of associated allergy are usually the mainstays of treatment.
  • Specific antibody deficiency (SAD)
  • • Though the prevalence of this disease is not known, it is a commonly found deficiency in patients with recurrent sinopulmonary infections. SAD is characterized by normal levels of antibodies with an inability to make antibody to polysaccharide vaccines. As with most humoral immune deficiencies described, recurrent sinopulmonary infections are the hallmark.
    • No consensus exists as to how many pneumococcal serotypes should be elicited to in order to fit into this disorder.
    • 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. 
    • A positive response has been variably defined as a titer to a specific serotype greater than 1.3 mg/mL or a 4-fold increase in preimmunization titers. 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 pneumococcal vaccines, neo-antigen responses may be difficult to determine because prevaccination titers were not available to determine antibody increases, and no consensus exists about what values constitute protective titer levels in patients who only have postvaccination titers. Meningococcal, polio, and typhoid vaccines are other potential neo-antigens that can be used to assess antibody responses. Antibody responses to polysaccharide antigens (eg, pneumococcal vaccine and HIB) in children aged younger than 2 years may be poor.
    • This entity should not be considered in children aged younger than 2 years. Patients who cannot mount a response to pure polysaccharide antigen (Prevnar) should be immunized with a conjugate pneumococcal vaccine (Pneumovax).
  • Common variable immunodeficiency (CVID)
  • • CVID is present in 1 in 50,000-75,000 people. CVID is so named because it is the most common primary immune deficiency. Variability, implied by the name, relates to the magnitude and classes of deficient serum immunoglobulins and also to the clinical course.
    • Individuals with this entity typically have recurrent upper and lower respiratory tract infections with encapsulated (HIB, pneumococcal, meningococcal) and atypical (Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila) organisms. Afflicted individuals also typically have recurrent sinusitis and bronchitis and may also have 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 and Giardia and Salmonella species. Viral hepatitis and severe cytomegalovirus enteritis may also occur. 
    • Patients with CVID are at increased risk for autoimmune diseases, as well. An estimated 20% of persons with CVID have some autoimmune manifestation, the most common being autoimmune thrombocytopenic purpura and autoimmune hemolytic anemia. 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 as well as other malignancies.
    • This diagnosis should be entertained only in patients older than 2 years.
    • While no pathognomonic physical examination finding is typical, lymphadenopathy, splenomegaly, or hepatomegaly can all be present. Abnormal lung examination indicating bronchiectasis indicates 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 decreases in levels of IgG, IgA, and IgM, some patients may have decreases in levels of only IgG. Low levels of B cells can also be seen. Impaired T-cell function can also be observed due to abnormal signal transduction. 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 eMedicine article Common Variable Immunodeficiency.
  • • Mutations or deficiency of the molecules or genes BTK, SHD1A, ICOS, and TNFSF5 have all resulted in the phenotype categorized as CVID. The treatment is regular IVIG and, when indicated, antimicrobial therapy.
  • Transient hypogammaglobulinemia of infancy
  • • Transplacentally-acquired maternal immunoglobulins naturally degrade over several months (the half-life of immunoglobulins is 21 days). Some infants experience a delay in endogenous production of antibodies for up to 3 years. Subsequently, normal antibody production resumes. During this trough of protective antibodies, children are susceptible to recurrent sinopulmonary infections and frequent viral illnesses. These children typically have a higher incidence of atopic diseases.
  • • IgG levels below the 5th percentile for age is the sine qua non of this entity. Decreased levels of IgA and, less frequently, IgM can also be seen. Most children have normal responses to protein vaccines, though poor responses have been reported.
    • 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 IVIG is undertaken because of intolerance or ineffectiveness of the antibiotics, it should be temporarily stopped every 3-6 months to assess endogenous production of immunoglobulins.
  • Immunodeficiency with thymoma (Good syndrome): Of patients with thymoma, 6-11% also have hypogammglobulinemia. 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 an emergent situation, as precipitous decline in clinical condition can occur. Patients present in the earliest weeks to months of life and succumb to opportunistic infections. 

• • • On physical examination, absence of lymphoid tissue and undetectable thymus shadow on chest radiograph are typical.  Peripheral erythrodermia is typical of a SCID variant called Omenn syndrome.
    • In addition to panhypogammaglobulinemia, age-adjusted lymphopenia, 1 or more reduced or absent lymphocyte populations, and profoundly reduced T-cell mitogenic response are also seen.
    • This is a heterogeneous group with multiple potential defective molecules that confer variable severity of illness. Defective molecules include cytokine receptor common gamma chain; 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 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.
    • Bone marrow transplantation should be undertaken as early as possible, since this has been shown to be a significant factor in improving overall survival. IVIG should be used, as well. 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.
    • 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 bone marrow transplant. Prior to bone marrow transplantation, patients with WAS are treated with prophylactic antibiotics, splenectomy, and IVIG.
  • Ataxia-telangiectasia (A-T)
  • • Patients with A-T present with gait ataxia, oculocutaneous telangiectasias, growth retardation, and immune deficiency.
    • 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.
    • The ATM gene and the protein nibrin are responsible for this disorder. 
    • Decreased or increased immunoglobulin levels, 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 IVIG, 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, 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.
  • • 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 may all be reduced in severe protein-losing enteropathy.
  • 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 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 treatment in neoplastic disease treatment 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. Tumor cells provoke several alterations to normal regulatory T cells, which impairs 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 PCs of patients with CLL, leading to PC apoptosis and, subsequently, to hypogammaglobulinemia.
  • Prematurity in infants
  • Drug-related: Seizure medications such as phenytoin and carbamazepine may cause reversible hypogammaglobulinemia. Chlorpromazine, phenytoin, carbamazepine, valproic acid, D-penicillamine, sulfasalazine, and hydroxychloroquine have been implicated in IgA deficiency.

Complement Deficiencies

Other Problems to be Considered

Other conditions may lead to chronic or recurrent airway infections. The following should be considered:
Respiratory allergies
Complement deficiencies
Ciliary dysmotility disorders
Cystic fibrosis

Lab Studies

• The evaluation of patients with suspected hypogammaglobulinemia should include quantitative measurement of serum Igs. If these are normal and a humoral immunodeficiency still is suggested, antibody response to specific antigens (polysaccharide and protein antigens) should be determined. The impaired antibody responses to various pathogens in hypogammaglobulinemic states may make serological diagnosis of certain infections (eg, HIV) difficult. In these patients, viral detection methods may be the best diagnostic tests for certain viral infections.
• Levels of serum immunoglobulin
• • 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 should be compared with age-standardized reference ranges.
  • In most disorders involving IgG, the level is below 200-250 mg/dL, with variable levels of the other Igs, depending on the underlying disease.
  • Serum IgA is less than 5 mg/dL, with normal IgG and IgM levels in selective IgA deficiency. IgG2 and IgG4 also may be decreased, especially in patients with sinopulmonary infections.
  • In hyper IgM syndromes, IgM is markedly increased to levels frequently higher than 1000 mg/dL. Levels of IgG, IgA, IgE, and the lymphocytes bearing these antibodies are decreased. IgM response to antigens is possible, but the 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, pneumococcal vaccination is used to detect a significant rise in antibody titers compared to prevaccination titers. Vaccine-associated antibodies should be determined if the titers for total Igs are normal and specific antibody deficiency is suspected. Pneumococcal immunization should be repeated if the response is inadequate after the first immunization.  
• Isohemagglutinins
• • IgM antibodies to A and 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. Blood antigen responses, which normally develop in the first year of life, are not normally present if the patient has AB blood type.
  • 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 (DTH) 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 after glucocorticoid therapy.
    • The test is read by measuring the induration 48-72 hours following an intradermal injection of 0.1 mL of tetanus toxoid (at 1:100 dilution, 0.2 Loeffler units/0.1 mL), mumps skin test antigen, 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 is considered positive if the induration is greater than 5 mm (or >2 mm in children).

• Complete blood count (CBC): The CBC may indicate lymphopenia or lymphocytosis, which may be seen with secondary causes of hypogammaglobulinemia (intestinal lymphangiectasia and CLL, respectively). Immunophenotypic lymphocyte studies may be required to diagnose CLL.
• Renal studies: Renal disease in which protein loss causes hypogammaglobulinemia is easily diagnosed by urinary quantitation for total 24-hour urinary protein level.
• 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 utilizing 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. 

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.
  • 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 ADA deficiency.

• High-resolution computed tomography and nuclear scanning
• • HRCT scans may uncover important lung abnormalities in patients with CVID and primary hypogammaglobulinemia. 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 helping detect silent or asymptomatic structural changes of airways and lung parenchyma that sometimes occur despite appropriate IVIG therapy.
  • Imaging studies of the abdomen may show organomegaly. Splenomegaly may be observed in CVID in the absence of lymphoma or lymphoproliferative disease.

Other Tests

• Adenosine deaminase (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 is a defect in nucleoside phosphorylation; this should be evaluated along with ADA levels. Tests can be done prenatally on amniotic fluid. B cells and T cells are absent in autosomal recessive SCID.
• For Wiskott-Aldrich syndrome, sequence analysis determines 99% of mutations known to cause the disease entity. Absent or decreased Wiskott-Aldrich syndrome protein (WASP) can be determined by flow cytometry or western blotting
• Prenatal diagnosis of XLA, XHM, WAS, and ADA deficiency can be accomplished by 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 a 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 XSCID. "BALD" lymphocytes found on scanning electron microscopy is diagnostic of WAS. Red blood cell ADA is decreased in fetuses with ADA deficiency.
• Commercial labs 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 may be helpful in CVID and IgA deficiency by showing 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 XSCID 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.

Medical Care

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

Activity

Special restrictions on physical activity are not needed.

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

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

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

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

Drug Category: Immunoglobulins

Improve clinical and immunologic aspects of the disease.

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

Further Outpatient Care

• 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.
  • Pulmonary function tests should be performed.
  • Immunoglobulin trough level: levels higher or equal to 400 mg/dL are considered satisfactory. Occasionally, levels higher than 500 mg/dL are required to clear certain viral infections such as enterovirus meningoencephalitis. Trough levels may need to be titrated in individual patients to determine the level needed to prevent recurrent infection.
  • Liver function tests should be performed, and if abnormalities are identified, imaging studies of the liver and biliary tree are necessary to rule out malignancies or sclerosing cholangitis (the latter is seen in XHM).

In/Out Patient Meds

• IVIG therapy can be given at home once initiated.

Transfer

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

Deterrence/Prevention

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

Complications

• Spruelike syndrome with malabsorption is observed in 10% of patients with 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.
• Vaccine-associated poliomyelitis may occur in patients with XLA who receive the attenuated live poliovirus vaccine.
• Persistent enteroviral infection remains the major complication of patients with XLA.
• Viral encephalitis caused by, in decreasing order, enterovirus, coxsackievirus, measles, and papovavirus is a rare and devastating complication of hypogammaglobulinemia.
• Hearing loss due to chronic otitis media or meningoencephalitis may affect as many as one third of patients with XLA.
• Bronchiectasis and cor pulmonale complicate chronic/recurrent lower respiratory infections.
• Autoimmune diseases
• • The most common disorders are Coombs-positive hemolytic anemia and idiopathic thrombocytopenic purpura.
  • Neutropenia is observed less frequently.
  • Pernicious anemia occurs in 10% of patients with CVID and is characterized by a younger age of onset and an absence of antiparietal cell antibodies.
  • 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. However, 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. This entity should be differentiated from mycobacterial and fungal infections. In the small subset of patients with aggressive disease, corticosteroids and TNF inhibitors are the treatments of choice.
• Anaphylactic reactions can occur when patients with IgA deficiency receive blood products containing IgA.
• The risk of GVHD is high in patients with SCID due to their inability to reject foreign antigens.
• Dermatomyositislike 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 in this disorder.
• Complications related to intravenous immunoglobulin therapy
• • Nonanaphylactic reactions: The most common adverse reactions 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.
  • 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 together.

Prognosis

• 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.
  • Chronic lung and liver diseases result in significant morbidity and mortality.
  • 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.
  • For many of these disorders, patients do not survive beyond childhood unless a definitive treatment is performed. For example, patients with SCID die within the first year of life unless a bone marrow transplant is performed. If a bone marrow transplant is performed within the first 3 months of life, the chance of survival is approximately 93%.

Patient Education

• 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.

Medical/Legal Pitfalls

• Exercise special care to identify children with hypogammaglobulinemia to avoid liability from the use of live attenuated vaccines, which are contraindicated in this setting.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors James O Ballard, MD, and Issam Makhoul, MD, to the development and writing of this article.