eMedicine Specialties > Allergy and Immunology > Immunodeficiencies

Hypogammaglobulinemia

Author: Robert Y Lin, MD, Professor, Department of Medicine, New York Medical College; Chief, Allergy and Immunology Section, Medical Advisor, Department of Case Management/Utilization Review, St Vincent's Catholic Medical Centers, St Vincent's of Manhattan
Coauthor(s): Avi M Deener, MD, Fellow in Allergy and Immunology, Albert Einstein College of Medicine, Montefiore Medical Center; Jenny Shliozberg, MD, Associate Clinical Professor, Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine; Consulting Staff, Department of Pediatrics, Montefiore Hospital Medical Center and Albert Einstein College of Medicine; Director of Pediatric Allergy and Immunization Clinic, Children's Hospital at Montefiore Medical Center
Contributor Information and Disclosures

Updated: Oct 10, 2007

Introduction

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.

Clinical

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.

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• Transient Hypogammaglobulinemia of Infancy (Pediatrics: General Medicine)
• Agammaglobulinemia (Pediatrics: General Medicine)
• Lymphoproliferative Syndrome, X-linked (Hematology)
• Pure B-Cell Disorders (Hematology)

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