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Hypogammaglobulinemia Clinical Presentation

  • Author: Robert Y Lin, MD; Chief Editor: Michael A Kaliner, MD  more...
 
Updated: Apr 21, 2014
 

History

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

Family history

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

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

Age of onset

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

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

Site of infections

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

Type of microorganisms

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

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

Blood product reactions

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

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

Recurrent infections

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

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

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

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

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

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

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

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

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

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

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

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

Gastrointestinal symptoms

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

Gastritis with achlorhydria and pernicious anemia may occur.

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

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

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

Musculoskeletal symptoms

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

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

Autoimmune and collagen vascular diseases

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

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

Reactions to blood products

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

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

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Physical

See the list below:

  • Growth retardation: Early-onset recurrent infections and GI problems associated with immune deficiencies can cause growth retardation. However, the presence of normal growth does not rule out these disorders. Giardiasis and other GI problems may cause weight loss in adults.
  • Lymphoid tissue and organs
    • A paucity of tonsillar tissue, adenoids, and peripheral lymph nodes is seen in XLA and combined T-cell/B-cell deficiencies and should provide important clues to their diagnosis.[5]
    • Diffuse lymphoid hyperplasia may accompany CVID and some hyper-IgM syndromes, and splenomegaly with or without hypersplenism occurs in 25% of patients with CVID. Lymph node biopsy from patients with CVID may show the absence of follicles and germinal centers with a relative paucity of plasma cells, or reactive hyperplasia may be present. The stomach and/or intestines may have hypertrophic folds and/or lymphoid hyperplasia in CVID.
  • Developmental abnormalities: Skeletal and chest wall abnormalities affecting the vertebral bodies and the chondrocostal junctions occur in patients with adenosine deaminase deficiency.
  • Skin and mucous membranes
    • Permanent scars can occur following skin infections.
    • Severe eczematoid rash is typical of WAS.
    • Livedo reticularis with muscle weakness or a dermatomyositis-like syndrome may present with XLA.
    • A lupuslike rash may occur.
  • Ear, nose, and throat
    • Tympanic membrane perforation or scarring, with hearing loss, can occur because of recurrent otitis media. Purulent nasal discharge, a cobblestone pattern of pharyngeal mucosa, and nasal exudate usually are present, consistent with chronic sinusitis, which is one of the most common findings in these patients.
    • Note the presence or absence of tonsillar tissue.
  • Pulmonary
    • Recurrent bronchitis and pneumonias can lead to bronchiectasis and lung fibrosis.
    • Rales, rhonchi, and wheezing can be observed on lung examination in such patients.
    • Digital clubbing may result from chronic obstructive pulmonary disease (COPD).
  • Cardiovascular system
    • Chronic respiratory insufficiency can result in pulmonary hypertension and, eventually, right-sided heart failure.
    • 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 attenuated poliovirus vaccine, although live polio vaccinations are no longer used in the United States.
    • Deep sensory loss with decreased vibratory and position sense of limb segments is seen in pernicious anemia.
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Causes

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

  • Primary or congenital B-cell disorders
    • X-linked agammaglobulinemia (XLA, Bruton agammaglobulinemia)
      • Patients with XLA have recurrent bacterial infections, including otitis media, sinusitis, and pneumonia. In the modern era of immunization, the prevalence of formerly common viral infections of childhood is so low that even undiagnosed XLA patients may not develop these infections despite their lack of protective immunity. Approximately 85% of male patients with frank 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 chronic meningoencephalitis due to enterocytopathogenic human orphan (ECHO) viruses. Other clinical entities observed are P carinii pneumonia, and U urealyticum arthritis and bacteremia.
      • Family history suggestive of X-linked transmission is typical, though sporadic cases are actually more frequent than familial cases.[5] Bronchiectasis and gastroenteritis may develop over time with this ailment despite aggressive treatment. Small or absent tonsils and peripheral lymph nodes are the only consistent findings on physical examination, but they are characteristic and often missed.
      • 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%.[7]
      • This entity is usually identified within the first 2 years of life but the diagnosis is often missed until later in childhood.[5]
      • Mutations in the Bruton tyrosine kinase (BTK) gene and protein have been implicated in this entity.[1, 5] Different mutations confer variable severity of illness, and direct sequencing is sometimes required for definitive diagnosis. The treatment includes regular IgG replacement with intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) and antimicrobial therapy. For cases in which bronchiectasis is present, inhaled antibiotics, bronchodilators, and measures to improve clearance of secretions (eg, percussion vests and postural drainage) may be helpful.
    • Autosomal recessive agammaglobulinemia (ARA)
      • Generally, the only differences between ARA and XLA, other than occurrence of the former in females, are the pattern of inheritance and the genes implicated. The clinical presentation, lab abnormalities, age at onset, and treatment of ARA are identical to those of XLA.
      • The implicated molecules or genes include IgM heavy chain, Ig alpha, surrogate light chain, B cell linker protein (BLNK), and leucine-rich repeat – containing 8 (LRRC8) in different patients.
    • Hyper-IgM syndromes (including deficiencies of CD40 ligand (CD154), activation-induced cytidine deaminase [AID], and uracil-nucleoside-glycosylase [UNG]): This is a heterogeneous group of disorders in which normal or elevated IgM levels are found along with low levels of IgA, IgG, and, sometimes, IgE. One X-linked form of hyper IgM is associated with CD40 ligand (CD154) defects and may have impaired T-cell function and associated opportunistic infections.[8] CD154 is actually a co-stimulatory molecule expressed by activated T-cells which helps induce immunoglobulin isotype switching in B-cells. CD40-CD154 interactions are also important for communication between dendritic cells and T-cells, and between T-cells and macrophages. Patients 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 form in which CD40 ligand (CD154) is deficient. AID and UNG deficiencies both result in the hyper-IgM phenotype. These molecules are involved in DNA processing steps necessary for class switching and somatic hypermutation in B cells.
      • Regular IgG replacement therapy is effective at reducing bacterial infections in these patients if they are deficient in IgG but may not prevent fungal/protozoan infections in CD154 deficiency.
    • Isolated non-IgG immunoglobulin deficiencies (IgM, IgA)
      • IgA deficiency is defined as an absent IgA level with normal IgG and IgM levels in patients older than 4 years in whom other reasons for hypogammaglobulinemia have been ruled out. 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 occasionally in association with IgA deficiency.
      • No molecular or genetic basis for most cases of this disorder is known.
      • Treatment with IVIG or SCIG is usually not necessary, unless a concomitant clinically significant IgG subclass of specific antibody deficiency is present. Commercial pooled IgG preparations have no significant quantity of IgA. Using immunoglobulin replacement is not recommended in IgA deficiency, as it provides no clinical benefit. Use of IVIG or SCIG in subclass deficiency is likewise not recommended, unless substantial and clinically important specific antibody deficiency is thought to be the cause of recurrent infections.[9, 10]
    • IgG subclass deficiency
      • This syndrome is defined as one or more IgG subclasses at 2 standard deviations below the mean, with normal total IgG and IgM levels. IgA levels may also be low.
      • Whether this entity should be categorized under the CVID heading is controversial. By definition, 2.3% of the "normal" population fits such a classification. A few case series report these patients having recurrent sinopulmonary infections and environmental allergies.
      • In addition to the criteria noted above, the response of these patients to immunization with polysaccharide antigens is often poor or absent, leading to the diagnosis of specific antibody deficiency. The inability to mount an antibody response to infection may be seen more commonly in children because development of the ability to respond to polysaccharides often lags behind development of protein responses.[11, 12] Infections in many of these patients are deemed insufficiently severe to warrant the expense of IgG replacement therapy. Hence, prophylactic antibiotics and treatment of associated allergy are usually the mainstays of treatment.
      • Rarely, adults with recurrent sinopulmonary infections are found to have the inability to create antibodies to Pneumovax upon repeated immunizations.[12] Such patients are thought to have specific antibody deficiency, and some physicians try immunoglobulin replacement as a treatment, but no clinical trials of treatment have been published supporting this approach.
    • Specific antibody deficiency (SAD) or specific polysaccharide antibody deficiency (SPAD)
      • Though the prevalence of this condition is not known, it is occasionally found in patients with recurrent sinopulmonary infections. SAD is characterized by total levels of IgG, IgA, and IgM within the normal range, but with an inability to make appropriate quantities of specific antibodies and/or to retain memory of polysaccharide vaccines. As with most humoral immune deficiencies described, recurrent sinopulmonary infections are the hallmark.
      • No consensus exists as to the titer or number of pneumococcal serotype antibody responses that should be elicited in order to fit into this disorder.[12]
      • Age must be considered when entertaining this diagnosis. While no reliable age-adjusted criteria for polysaccharide response exists, the general guideline is that the younger the patient, the fewer the responses. The diagnosis should not be assigned to children younger than 2 years, because IgG2, IgA, and specific polysaccharide responses usually develop more slowly than other types of antibody response.
      • A positive response is usually defined as a titer to a specific serotype greater than 1.3 mg/mL or a 4-fold increase in preimmunization titers.[12] Some authors suggest that at least 3 serotypes showing specific antibody levels ≥2 µg/mL probably represents a normal antibody responsiveness, while others suggest that 9 out of 12 serotype responses is considered normal.
      • In patients who have already been vaccinated with conjugated pneumococcal vaccines, the actual response may be difficult to determine because prevaccination titers were not available to determine antibody increases, and no consensus exists about what values constitute protective titers in patients who only have postvaccination titers. Meningococcal and typhoid vaccines are other potential antigens that can be used to assess antibody responses.[11, 12] Antibody responses to polysaccharide antigens (eg, unconjugated pneumococcal polysaccharide vaccine) in normal children younger than 2 years are often poor, which is why protein conjugate vaccines are usually used in this age group.
    • Common variable immunodeficiency (CVID)
      • CVID is present in 1 in 5,000-7,000 people. CVID is so named because it is the most common primary immune deficiency.[3, 4] Variability, implied by the name, relates to the magnitude and classes of deficient serum immunoglobulins and also to the clinical course. CVID is usually differentiated from XLA and autosomal recessive agammaglobulinemia by the presence of B-cells, visible tonsils or a history of tonsillectomy, and palpable or even enlarged lymph nodes.
      • Individuals with CVID typically have recurrent upper and lower respiratory tract infections with encapsulated bacteria such as haemophilus, pneumococcus, staph, and meningococcus as well as and atypical bacterial pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Individuals with CVID also typically have recurrent sinusitis and bronchitis, and they frequently develop bronchiectasis, granulomatous lung disease, and lymphocytic interstitial pneumonitis. Gastrointestinal complications are also typical, including lymphonodular hyperplasia, inflammatory bowel disease, and nonspecific malabsorption. Enteric infections also occur; the most common are Campylobacter jejuni, Helicobacter pylori, and Giardia and hemolytic anemia.[4] One third of patients develop a lymphoproliferative disorder, includingsplenomegaly, generalized lymphadenopathy, or intestinal lymphoid hyperplasia. These patients are at 30- to 400-fold increased risk for developing non-Hodgkin lymphoma and other malignancies.[4]
      • This diagnosis should not be assigned to patients younger than 2 years, in whom hypogammaglobulinemia may represent a delay in the maturation of B-cell responses.
      • While no pathognomonic physical examination finding is typical, lymphadenopathy, splenomegaly, and/or hepatomegaly can all be present. Abnormal lung examination indicating bronchiectasis suggests long-standing disease. A patient could also have positive Hemoccult test results secondary to invasive bacterial infection.
      • Hallmarks of the disease are hypogammaglobulinemia and impaired specific antibody response to vaccination. Although patients with CVID classically have decreased levels of IgG, IgA, and IgM, some patients may have decreases in levels of only IgG, and some have elevated levels of IgM. Most patients with CVID have a normal number of B cells, but, in approximately one third of patients, the number of B cells with surface immunoglobulin is lower than normal. More detailed description of cellular abnormalities and related testing are described in the Medscape Reference article Pediatric Common Variable Immunodeficiency.
      • About 10 percent of patients have a family history of at least one relative with CVID or selective IgA deficiency, with autosomal dominant or recessive inheritance patterns. The remaining cases are believed to arise from sporadic mutations, although, in most cases, no such mutation has yet been identified. Defects in the molecules ICOS, TACI, and BAFF-R can apparently all result in phenotypes categorized as CVID, but the number of such mutations identified explains only a small percentage of CVID patients, and non – disease-causing polymorphisms are frequent.[13] The mainstays of treatment are regular IgG replacement (IVIG or SCIG) and, when indicated, antimicrobial therapy. However, many CVID patients require corticosteroids to control autoimmune manifestations, and splenectomy is not uncommon
    • Transient hypogammaglobulinemia of infancy
      • Transplacentally-acquired maternal IgG is metabolized over several months (the half-life of immunoglobulins is 21 days) and usually falls below 0.3 to 0.4 g/L by 6 months of age. Normal infants begin making IgG shortly after birth; in some babies, this is delayed, but B-cells are present and IgG production eventually normalizes. Inadequate endogenous IgG production may remain in a prolonged deep trough at the nadir of the IgG levels, leaving the child susceptible to gastrointestinal infections, recurrent sinopulmonary infections, and frequent viral illnesses. In turn, these infections may present physiologic challenges to the vulnerable infant, further impairing the development of protective responses. Because of the rapidity of physiologic changes between ages 4 and 12 months, the trend across several IgG levels is likely a better prognostic indicator than any single level at one point in time.
      • IgG levels persistently below the 5th percentile for age is the sine qua non of this entity. Decreased levels of IgA are also common in this group, and low IgM levels may be seen, but less frequently. Most of these babies have normal lymphocyte counts for age and normal lymphocyte mitogen stimulation test results, and their IgG responses to initial protein vaccines such as DPT are frequently normal.
      • While no specific mechanism has been identified for this entity, its incidence is increased in families with other immunodeficiencies. This association suggests a genetic component
      • Generally, only prophylactic antibiotics are needed to protect these individuals. If IgG therapy is started because of intolerance or ineffectiveness of the antibiotics, it should be temporarily stopped every 3-6 months to re-assess endogenous production of immunoglobulins.
    • Immunodeficiency with thymoma (Good syndrome): Of patients with thymoma, 6-11% also have immunodeficiency, most commonly in the form of hypogammaglobulinemia. The concomitant occurrence of these conditions is termed Good syndrome. However, hypogammaglobulinemia often does not resolve with successful treatment/resection of the thymoma, and associated T-cell abnormalities may exist.
  • Combined T-cell and B-cell disorders
    • Severe combined immunodeficiency (SCID)
      • SCID, as its name implies, is the most severe of the pediatric immunodeficiencies. Suspicion of SCID is a truly emergent situation, as precipitous decline in clinical condition can occur with any infectious challenge. Neonates with SCID are usually indistinguishable from normal newborns, prompting a call for newborn screening so SCID can be detected before a potentially fatal infection occurs. Lymphopenia is characteristic of SCID, but age-specific norms must be used, since normal newborns should have higher lymphocyte counts than older children and adults.[1, 14]
      • On physical examination, absence of lymphoid tissue and undetectable thymus shadow on chest radiograph are typical. Erythroderma combined with lymphadenopathy and hepatosplenomegaly is typical of a SCID variant called Omenn syndrome.
      • In addition to age-adjusted lymphopenia, one or more reduced or absent lymphocyte populations and profoundly decreased T-cell mitogenic responses are also observed. An exception to this may occur if engraftment of maternal lymphocytes before birth has occurred, resulting in a form of graft versus host disease (GVHD). IgG levels are frequently normal within the first couple of months of life, since this is maternally derived.
      • SCID is a heterogeneous group of conditions caused by different mutations that interfere with development of T-cells, and, in some cases, B-cells and NK cells as well.[1] The most common mutations are in the cytokine receptor common gamma chain (in X-linked SCID); the common IL-2 and IL-7 receptor alpha chain; Janus tyrosine kinase-3 (JAK3); CD45; CD3 subunits gamma, delta, and epsilon; recombinase-activating gene proteins 1 and 2 (RAG-1, RAG-2); DNA cross-link repair protein 1C; adenosine deaminase; purine nucleoside phosphorylase; transporter 1 and 2, ATP-binding cassette (TAP1, TAP2); 4 components of major histocompatibility complex (MHC) class II gene transcription complex; and winged-helix nude transcription factor.
      • Hematopoietic stem cell (bone marrow) transplantation (HSCT) should be undertaken as early as possible and has been successful in up to 95% of cases in which it has been performed before 30 days of life.[1, 14] IgG replacement should be used, as well, and is usually continued for at least 12 months because B-cell engraftment and development after transplantation is usually delayed. These individuals should also be protected from exposure to infectious agents. Prophylaxis against P carinii is also recommended.
    • Wiskott-Aldrich syndrome
      • Classically, patients with Wiskott-Aldrich syndrome (WAS) present with eczema, petechiae, bruising or bleeding, recurrent severe infections (including opportunistic infections) autoimmune diseases, and B-cell lymphomas. X-linked inheritance is exhibited.[8]
      • Thrombocytopenia and small platelet size are usually seen on routine blood work results. Low levels of IgG, IgM, and IgE and, sometimes, elevated IgA levels, as well as impaired specific antibody production, are also seen. T-cell abnormalities are also seen, including lymphocytopenia and impaired T-cell function.
      • WAS protein mutations define this entity.
      • The only curative treatment is hematopoietic stem cell (bone marrow) transplantation. Prior to bone marrow transplantation, patients with WAS are treated with prophylactic antibiotics, splenectomy, and IVIG. While gene therapy remains unproven for WAS at this time, good clinical and laboratory results have been observed in a few patients.[15]
    • Ataxia-telangiectasia (A-T)
      • Patients with A-T develop gait ataxia, oculocutaneous telangiectasias, growth retardation, and immune deficiency. However, this diagnosis may not be apparent early because many of these signs and symptoms develop slowly with time and/or may present with regressive loss of developmental milestones, and thus may be difficult to recognize.
      • Clinical immunodeficiency is seen in infancy or early childhood. Growth retardation and delay in gross motor coordination are also seen. Oculocutaneous telangiectasias do not typically appear until patients are aged 3-5 years, so they are not useful in making an early diagnosis.
      • Mutations in the ATM gene and the protein it encodes, nibrin, are responsible for this disorder. The mutations result in defective DNA repair and increased susceptibility to ionizing radiation. Therefore, radiography should be minimized, and the risk of malignancy is very high.
      • IgA deficiency, IgG subclass deficiencies, impaired specific antibody response, and derangement in lymphocyte population are typical of A-T. Elevated levels of alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) are seen in 95% of patients with A-T and are virtually pathognomonic.
      • Antibiotic prophylaxis, as well as IgG replacement, is appropriate for the treatment of the immunodeficiency aspect of this syndrome. A multidisciplinary approach to the patient as a whole should be undertaken to address the multisystem nature of this disease.
  • Secondary or acquired diseases
    • Nephrotic syndrome: Decreased levels of IgG can appear with normal levels of IgA and IgM in the nephrotic syndrome.
    • Protein-losing enteropathy
      • Intestinal lymphangiectasia, which is sometimes considered as a subset of protein-losing enteropathies, frequently causes not only loss of protein, but also of B-cells, leading to lymphopenia. This occurs because of intestinal lymphatic blockade with resulting leakage of lymphatic fluid and cellular components into the lumen.
      • Both nephrotic syndrome and protein-losing enteropathies manifest with hypoalbuminemia and, usually, edema. IgG levels are affected more than IgM or IgA levels in protein-losing enteropathies. However, levels of IgG, IgM, and IgA, and the cells that produce them, may all be reduced in severe protein-losing enteropathy.
    • Catabolic disorders: Increased catabolism occurs in various diseases, including the B-cell lineage malignancies, severe burns, and myotonic dystrophy.
    • Immunosuppressive therapy
      • Immunosuppressant medication can cause hypogammaglobulinemia, especially in the setting of solid organ transplantation. Long-term corticosteroid treatment can also result in hypogammaglobulinemia, which may, rarely, be symptomatic. Patients with asthma and with hypogammaglobulinemia secondary to corticosteroid use retain specific antibody responses and, thus, are not necessarily candidates for immunoglobulin replacement therapy. Patients presenting with sinusitis and/or bronchitis with secondary bronchospasm, however, may have CVID or other forms of antibody deficiency that will respond to IgG replacement. Patients who take daily doses of ≥12.5 mg prednisone for 1 year or more are more likely to have hypogammaglobulinemia.
      • Immunosuppressants combined with corticosteroids may create an even greater propensity toward hypogammaglobulinemia. Such treatments are commonly used in patients with autoimmune and neoplastic diseases. Rituximab (anti-CD20) treatment in neoplastic and/or autoimmune disease also may be associated with hypogammaglobulinemia. Chemotherapy, autologous stem cell transplantation, or both may contribute to the hypogammaglobulinemia.
      • Although malnutrition and radiation have been purported to cause secondary hypogammaglobulinemia, the literature supporting this association is weak. For example, studies on malnourished African children showed that cellular immunity was much more impaired than humoral immunity. Total lymphoid irradiation used in the past for rheumatoid arthritis did not decrease rheumatoid factor levels, suggesting that nonmyeloablative irradiation has little effect on immunoglobulin levels. Thyrotoxicosis is not associated with hypogammaglobulinemia.
    • Lymphoproliferative malignancies
      • Chronic lymphocytic leukemia: B-cell chronic lymphocytic leukemia (B-CLL) is often associated with hypogammaglobulinemia and infections.[16] Multiple myeloma and other monoclonal gammopathies may result in antibody deficiency in the face of apparently normal total IgG levels because of the contribution of the paraprotein to the total IgG level. Tumor cells provoke several alterations to normal regulatory T cells, which impair the correct maturation of B cells.
      • B-CLL cells also directly inhibit Ig-secreting plasma cells (PCs), which may account for the humoral immunodeficiency. This phenomenon is mediated by the interaction of CD95L molecules expressed by B-CLL cells with the death receptor CD95 that is up-regulated on the plasma cells of patients with CLL, leading to increased plasma cell apoptosis and, subsequently, to hypogammaglobulinemia. Treatment of CLL-associated hypogammaglobulinemia with IgG replacement may have only marginal benefit unless specific antibody deficiency has actually been demonstrated.[16]
    • Prematurity in infants: Babies born before completion of the third trimester in utero frequently lack adequate maternal immunoglobulin and may also have more rapid metabolism of what IgG they have received.
    • Drug-related: Anti-seizure medications such as phenytoin, carbamazepine, and lamotrigine may cause reversible hypogammaglobulinemia. Chlorpromazine, phenytoin, carbamazepine, valproic acid, D-penicillamine, sulfasalazine, and hydroxychloroquine have been implicated in IgA deficiency.
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Contributor Information and Disclosures
Author

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

Robert Y Lin, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, New York Allergy & Asthma Society

Disclosure: Nothing to disclose.

Coauthor(s)

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

Jenny Shliozberg, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, International AIDS Society

Disclosure: Nothing to disclose.

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

Amit J Shah, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

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

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

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

Michael R Simon, MD, MA is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, Michigan State Medical Society, Michigan Allergy and Asthma Society, American College of Physicians, American Federation for Medical Research, Royal College of Physicians and Surgeons of Canada, Society for Experimental Biology and Medicine

Disclosure: Received ownership interest from Secretory IgA, Inc. for management position; Received ownership interest from siRNAx, Inc. for management position.

Chief Editor

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

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Additional Contributors

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

Melvin Berger, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Clinical Investigation, Clinical Immunology Society

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

Acknowledgements

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

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