Hypogammaglobulinemia refers to a set of clinicolaboratory entities with varied causes and manifestations. The common clinical feature of hypogammaglobulinemia relates to a predisposition toward infections that normally are defended against by antibody responses (including Streptococcus pneumoniae and Haemophilus influenzae infections).
Signs and symptoms
Most patients with hypogammaglobulinemia present with a history of recurrent infections. A detailed clinical history should emphasize the following:
Age of onset
Site of infections
Type of microorganisms
Blood product reactions
Autoimmune and collagen vascular diseases
Physical findings may include the following:
Abnormalities of lymphoid tissue and organs (eg, a paucity of tonsillar tissue, adenoids, and peripheral lymph nodes)
Developmental abnormalities (eg, of skeleton or chest wall)
Abnormalities of skin and mucous membranes (eg, scars, rash, or livedo reticularis)
Ear, nose, and throat abnormalities (eg, tympanic membrane perforation, purulent nasal discharge, cobblestone pattern of pharyngeal mucosa, and nasal exudate)
Pulmonary abnormalities (eg, bronchiectasis and lung fibrosis with rales, rhonchi, and wheezing)
Cardiovascular abnormalities (eg, a loud pulmonic heart sound, right ventricular heave, and tricuspid regurgitation murmur suggesting pulmonary hypertension; jugular venous distention, tender hepatomegaly, and lower-extremity edema suggesting cor pulmonale)
Neurologic abnormalities (eg, paralytic poliomyelitis or deep sensory loss with decreased vibratory and position sense of limb segments)
See Clinical Presentation for more detail.
Laboratory studies that may be helpful include the following:
Antibody response after immunization
Peripheral blood lymphocyte immunophenotyping
Evaluation of cellular immunity (cutaneous delayed-type hypersensitivity)
Complete blood count
GI studies (eg, alpha1 -antitrypsin)
Imaging studies that may be useful include the following:
High-resolution computed tomography (HRCT) and nuclear scanning
The following tests may be considered as circumstances warrant:
Adenosine deaminase (ADA) levels and mutations in purine nucleoside phosphorylase
Flow cytometry or Western blotting
Restriction fragment length polymorphism (RFLP)
The following biopsy procedures may also be considered:
Lymph node biopsy (for rapidly enlarging lymph nodes to rule out infection or malignancy)
Rectal biopsy (for common variable immunodeficiency [CVID] and immunoglobulin A [IgA] deficiency)
Thymus biopsy (indicated only for thymoma)
See Workup for more detail.
Replacement therapy with immunoglobulin G (IgG), administered intravenously (IVIG) or subcutaneously (SCIG), is the treatment of choice for most primary immunodeficiency syndromes, including the following:
X-linked agammaglobulinemia (Bruton disease; XLA)
Severe combined immunodeficiency (SCID)
Wiskott-Aldrich syndrome (WAS)
Treatment of secondary hypogammaglobulinemia is directed at the underlying cause, as follows:
IVIG is not indicated for lymphoproliferative disorders unless immunoglobulin levels are low in association with recurrent infections or if IVIG is being used for autoimmune conditions that may accompany these disorders
Live vaccines should not be given to patients with T-cell disorders, XLA, or other severe B-cell disorders or to the family members of such patients
High doses of IVIG or intrathecal immunoglobulin may be beneficial in patients with XLA who have enteroviral meningoencephalitis
Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for SCID and, if a matched donor is available, for ADA deficiency
Enzyme replacement with polyethylene glycol-ADA (PEG-ADA) may be an effective alternative for patients with ADA deficiency who lack an HLA-identical sibling
Tumor necrosis factor (TNF) inhibitors have been used to treat granulomatous diseases in patients with CVID
Gene therapy has been shown to be successful in reconstituting immune function in infants with X-linked SCID, but efficacy is less proven in older children and young adults
Hypogammaglobulinemia refers to a set of clinicolaboratory entities with varied causes and manifestations. Several codes in the International Classification of Diseases, 9th edition (ICD-9) relate to disorders in which hypogammaglobulinemia is a primary feature. These include deficiencies of humoral immunity, which is coded 279.0. The common clinical feature of hypogammaglobulinemia relates to a predisposition toward infections that normally are defended against by antibody responses. These include Streptococcus pneumoniae and Haemophilus influenzae infections, which frequently involve the respiratory tract.
While primary immunodeficiencies causing hypogammaglobulinemia are relatively uncommon, the demand for gammaglobulin treatment has grown and placed demands on the limited supply of this treatment. Therefore, an awareness of the appropriate diagnostic and therapeutic approaches to hypogammaglobulinemia is important.
Specific immune responses are based on 2 major components, ie, (1) humoral immunity, involving antibodies produced by B lymphocytes also known as B cells, and (2) cellular immunity, requiring recognition by T lymphocytes or T cells. Immunoglobulins (Igs) produced by B cells play a central role in humoral immunity, and deficiency may result in dramatic consequences for the body's defense against infections. Disorders of the immune system that can result in hypogammaglobulinemia can involve B cells, T cells, or both.
The information in this article is not meant to be a comprehensive review but rather, a guide on the differential diagnoses of hypogammaglobulinemia. This article provides a review of the causes, clinical symptoms, diagnosis, complications, and treatment of the more common forms of hypogammaglobulinemia.
Immunoglobulins play crucial roles in the immune response by recognizing foreign antigens and triggering effector mechanisms and physiologic responses that attempt, and usually succeed, in eliminating the invading organism bearing that antigen. The human immune system is capable of producing up to 109 different antibody species to interact with a wide range of antigens. The known immunoglobulin isotypes, named after their heavy-chains, are IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE.
The structural diversity of Ig isotypes is reflected in their functions. IgG isotypes represent the major component (approximately 85%) of all antibodies in serum, and IgA predominates in secretions. By binding to receptors for their Fc regions, they mediate many functions, including antibody-dependent cell-mediated cytotoxicity, phagocytosis, and clearance of immune complexes. IgM plays a pivotal role in the primary immune response. IgM, IgG1, IgG3, and, to a lesser degree, IgG2, fix and activate complement by the classical pathway. Most types of phagocytes bear receptors for the Fc of IgG.
In general, IgG1 is the major component of the response to protein antigens (eg, antitetanus and antidiphtheria antibodies). IgG2 and some IgG3 are produced in response to polysaccharide antigens (eg, antipneumococcal antibodies). Some patients who lack IgG2 still respond to polysaccharide antigens. IgG3 seems to play an important role in the response to respiratory viruses. IgA and, to a lesser extent, IgM, produced locally and secreted by mucous membranes, are the major determinants of mucosal immunity. IgG is the only Ig class that crosses the placenta. This occurs mostly during the third trimester of pregnancy and provides the full-term infant with effective humoral immunity during the first months of life. The levels of maternal antibodies slowly fall because of catabolism, reaching nonprotective levels by about 6 months of age. During this time, the infant begins endogenous production of IgG.
With the advent of serum protein electrophoresis, the globulins were considered to be comprised of 3 major fractions, alpha being the fastest moving and gamma the slowest. The gamma-globulin fraction is primarily composed of immunoglobulins, of which IgG is the largest component, constituting about 80% of the serum immunoglobulins in normal plasma, and is distributed throughout the entire volume of extracellular fluid. Immunoglobulins are produced by plasma cells.
Catabolism of immunoglobulins occurs in a concentration-dependent manner, with higher concentrations being cleared faster. This phenomenon may have therapeutic implications: a specific, saturable Fc receptor (termed FcRn, which differs from phagocyte Fc receptors) is thought to promote cellular recycling of intact immunoglobulin molecules, preventing their catabolism by lysosomes and therefore prolonging their half-life in the circulation. Normal IgG molecules have a half-life of 21-28 days. Renal clearance occurs for immunoglobulin fragments, not intact molecules. These fragments may be elevated in certain disease states and may be detected, for example, as myeloma -associated Bence Jones proteins in the urine.
Acquired or secondary hypogammaglobulinemia usually involves a few general categories. The major types include medications, renal loss of immunoglobulins, gastrointestinal immunoglobulin loss, B-cell–related malignancies, and severe burns. Renal loss of immunoglobulins is exemplified by nephrotic syndrome, in which IgG loss is usually accompanied by albumin loss. Gastrointestinal loss occurs in protein-losing enteropathies and intestinal lymphangiectasia. Increased catabolism occurs in various diseases, including the B-cell lineage malignancies and severe burns but also in dystrophic myotonia.
Hypogammaglobulinemia may result from lack of production, excessive loss of immunoglobulins, or both. Congenital disorders affecting B-cell development can result in complete or partial absence of one or more Ig isotypes. The classic form of this type of disorder is Bruton agammaglobulinemia, also known as X-linked agammaglobulinemia (XLA). Because B, T, and natural killer (NK) cells share a common progenitor, defects occurring at early developmental stages may result in combined immunodeficiency involving all cell types, although defects further down the differentiation pathways may result in deficiencies of a single cell type only.
The symptoms depend on the type and severity of the Ig deficiency and the presence or deficiency of cellular immunity. In general, hypogammaglobulinemia results in recurrent infections with a restricted set of microorganisms primarily localized to the upper and lower airways, although bacteremia and GI infections can also occur. Patients with associated defects in cellular immunity usually present with opportunistic viral, fungal, or parasitic infections.
For a detailed discussion of inherited causes of hypogammaglobulinemia, see Pure B-Cell Disorders.
The incidence of genetically determined immunodeficiency is relatively low when compared with acquired immunodeficiency. Humoral immunity deficiencies represent 50% of all primary immunodeficiencies. IgA deficiency is the most common antibody deficiency syndrome, followed by common variable immunodeficiency (CVID). The incidence of these 2 disorders is estimated to be 1 case in 700 persons and 1 case in 5,000-10,000 persons of European ancestry, respectively. Selective IgM deficiency is a rare disorder. IgG4 deficiency is very common and is detected in 10-15% of the general population. It usually does not cause clinical hypogammaglobulinemia and usually is asymptomatic.
Patients with hypogammaglobulinemia experience an increased incidence of a large spectrum of infections starting at an early age.
In conditions in which B-cells are present, such as CVID, the risk of autoimmune disorders and cancer is increased, adding to the morbidity and mortality due to infection.[3, 4] Recurrent infections may ultimately lead to significant end-organ damage, particularly involving the respiratory system. Malignancies remain a major cause of death.
Patients with certain inherited disorders may not survive infancy or early childhood, and growth may be affected for those who survive. Patients with severe combined immunodeficiency (SCID) die before the second year of life if they do not receive allogeneic stem cell (bone marrow or cord blood) transplantation, 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, but many have relatively normal life spans if they are diagnosed and begin immunoglobulin replacement therapy in early childhood, before chronic lung infection begins. Most patients with Wiskott-Aldrich syndrome (WAS) die by the second decade of life if they don't undergo transplantation.
Although gene therapy, bone marrow transplantation, and immunoglobulin replacement with intravenous or subcutaneous immunoglobulin have had a significant impact on the natural history of these diseases, these therapies are costly and often require highly advanced facilities.
No racial or ethnic predilection is recognized.
In children, primary immunodeficiencies are more common in boys than in girls (male-to-female ratio of approximately 5:1). In adults, primary immunodeficiencies are diagnosed almost equally in both sexes (male-to-female ratio of approximately 1:1.4).
XLA, X-linked hyper-IgM syndrome, X-linked SCID, and WAS are X-linked disorders for which females are carriers and only males are affected. However, WAS may occur if skewed inactivation of the X chromosome occurs, resulting in an active X chromosome carrying the Wiskott-Aldrich mutation.
CVID and IgA deficiency affect both sexes equally. They may be familial and frequently are associated with autoimmune disorders.
Symptoms in XLA typically begin around 6 months of age, when the concentrations of maternal antibodies decline. However, this may vary considerably, depending in large part on the baby's exposure to other children carrying infectious organisms. Unfortunately, the diagnosis is often missed or delayed until significant morbidity has occurred. Some patients with atypical XLA mutations and others with autosomal hypogammaglobulinemia do not develop recurrent infections and laboratory abnormalities until adulthood and may be misdiagnosed with CVID or selective antibody deficiency.
Infections in SCID, including severe candidiasis, usually begin in the first months of life.
The symptoms of hyper-IgM syndromes usually begin during the first 2 years of life. Chronic cryptosporidia infection may be particularly problematic in X-linked hyper-IgM, and stem cell transplantation is best performed before this begins.
Patients with WAS start experiencing recurrent bacterial infections during the first year of life. The incidence of opportunistic infections, such as Pneumocystis carinii, increases with time as patients survive childhood.
Patients with reticular dysgenesis begin experiencing recurrent infections soon after birth. This ultimately leads to death in early infancy.
The age of onset of adenosine deaminase (ADA) deficiency is variable. Most patients are diagnosed during infancy. Because the failure of the immune system is gradual, some cases are not diagnosed until later childhood.
IgA deficiency may be asymptomatic in childhood, and patients are usually diagnosed in early adulthood.
CVID has a variable age of onset, usually occurring by the third decade of life. However, on average, CVID patients experience increased infections and other symptoms for 10 years before their diagnosis is recognized.
Ig deficiency with thymoma (Good syndrome) affects adults aged 40-70 years.
Most patients with hypogammaglobulinemia present with a history of recurrent infections. A detailed clinical history should emphasize the following:
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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. 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%.
This entity is usually identified within the first 2 years of life but the diagnosis is often missed until later in childhood.
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. 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.
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. 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.
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. 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. 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.
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. 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. 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.
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 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.
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.
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.
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.
Chronic lymphocytic leukemia: B-cell chronic lymphocytic leukemia (B-CLL) is often associated with hypogammaglobulinemia and infections. 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.
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.
The evaluation of patients with suspected hypogammaglobulinemia should include quantitative measurement of serum immunoglobulins. If these levels are normal and a humoral immunodeficiency still is suggested, antibody response to specific antigens (polysaccharide and protein antigens) should be determined.[10, 11, 12, 5] The impaired antibody responses to various pathogens in hypogammaglobulinemic states may make serological diagnosis of certain infections (eg, HIV, Epstein-Barr virus [EBV]) difficult. In these patients, nucleic acid detection methods (ie, PCR or reverse PCR) may be the best diagnostic tests for certain viral infections.
Perform serum protein electrophoresis for presumptive diagnosis of hypogammaglobulinemia or monoclonal protein. Quantitative methods using immunodiffusion or nephelometry are used for the precise measurements of each isotype of Ig. Enzyme-linked immunosorbent assay is used for IgE quantitation.
Values must be compared with age-standardized reference ranges.
Common variable immunodeficiency (CVID) is defined by IgG levels less than 2 standard deviations below the mean, with equally low levels of IgA, IgM, or both.[10, 14]
Serum IgA is less than 5 mg/dL, with normal IgG and IgM levels, in selective IgA deficiency. levels of IgG2 and IgG4 also may be decreased, especially in patients with sinopulmonary infections.
In hyper-IgM syndromes, IgM may be markedly increased to levels frequently higher than 1000 mg/dL. However, the level of IgM often gradually increases with time and may be normal in children. levels of IgG, IgA, IgE, and the lymphocytes bearing these antibodies are decreased. IgM response to antigens is possible, but IgG and IgA responses are absent or diminished.
Antibody response after immunization
Vaccination-associated antibodies to diphtheria, tetanus toxoid, and HIB are normally demonstrable in patients who have received these vaccines, reflecting memory B-cell responses. Neoantigen responses may better reflect a patient’s current ability to mount antibody responses.
Typically, immunization with unconjugated pneumococcal vaccine is used to assess the response to polysaccharides by comparison of pre- and post-immunization titers (generally, a 4-fold rise is considered adequate). Vaccine-induced antibodies should be determined 4-8 weeks after pneumococcal immunization. Pneumococcal immunization should be repeated if the response is inadequate after the first immunization, and remaining titers should be determined 8-12 months later, if impaired immunologic memory is suspected.
IgM antibodies to A and/or B blood group antigens should be checked if the other tests results are normal and the patient is unable to mount a response to specific antigens. Antibodies to blood group antigens A or B would not be expected to be present if the patient's blood group is A or B respectively, or AB. These antibodies normally develop in the first year of life in response to ingestion of cross-reacting animal antigens in food.
The production of these antibodies is normal in protein-losing states, in contrast to extremely low levels in XLA.
Peripheral blood lymphocyte immunophenotyping
Peripheral B cell levels are variable.
Their number is normal in 75% of patients with CVID, but their surface phenotype may be immature.
T-lymphocyte number and function are intact in most cases of pure B-cell disorders.
Reversal of the ratio of helper (CD4) to suppressor (CD8) T cells has been reported in CVID, leading to nonreactive delayed-type hypersensitivity (DTH) test results. In combined T-cell and B-cell disorders, peripheral T cells are absent or decreased, with negative DTH test results.
Evaluation of cellular immunity
Cutaneous delayed-type hypersensitivity
Delayed-type hypersensitivity testing helps evaluate the memory response of cellular immunity to a previously encountered antigen. This test is not reliable in children younger than 1 year, and the response frequently is suppressed following viral and bacterial infections and during or after glucocorticoid therapy.
The test is read by measuring the induration 48-72 hours following administration of mumps skin test antigen or candidal antigen (at 1:100 wt/vol dilution; if no reaction, use 1:10 dilution), tuberculin (0.1 mL containing 2-10 IU of purified protein derivative), and trichophytin (1:30 wt/vol dilution). The test result is considered positive if the induration is greater than 5 mm (or >2 mm in children). Aqueous tetanus toxoid is no longer available for anergy panel testing.
Complete blood count (CBC): The CBC may indicate lymphopenia or lymphocytosis, which may be seen with secondary causes of hypogammaglobulinemia (intestinal lymphangiectasia and chronic lymphocytic leukemia [CLL], respectively). The absolute lymphocyte count must be compared to age-specific norms because infants normally have higher counts than older children and adults. Immunophenotypic lymphocyte studies are useful in determining the most likely defect in infants with severe combined immunodeficiency (SCID) and may be required to diagnose CLL.
Renal studies: Renal disease in which protein loss causes hypogammaglobulinemia is easily diagnosed by quantitation of the total 24-hour urinary protein excretion.
Protein-losing enteropathy that causes hypogammaglobulinemia may be more difficult to diagnose. Increased alpha1-antitrypsin (which is not present in normal diet) loss in the stool can be quantified in a 24-hour clearance procedure. Alternatively, a nuclear scan using technetium 99m dextran can be used to diagnose and localize protein-losing enteropathy.
Intestinal lymphangiectasia, which is sometimes considered a subset of protein-losing enteropathies, manifests not only with protein loss but also with lymphopenia. This occurs because of intestinal lymphatic blockade with resulting leakage of lymphatic fluid and cellular components into the lumen. Imaging and endoscopy are useful in diagnosing intestinal lymphangiectasia. However, this is often a "patchy lesion," and the diagnosis may be difficult.
In many patients with CVID and primary hypogammaglobulinemia, recurrent or chronic infections lead to abnormal findings on chest radiograph, such as interstitial infiltrates, bronchiectasis, emphysema or bullae, and scarring. Chest radiograph findings may be normal despite the presence of structural abnormalities. CVID patients often have hilar adenopathy and/or granulomata.
Although chest radiograph is an appropriate follow-up test for these patients, some argue for the use of high-resolution computed tomography (HRCT) as the criterion standard.
The absence of a thymic shadow is a common finding in patients with SCID. Thymomas may be identified on chest radiograph in patients with Good syndrome.
Cupping and flaring of the costochondral junctions is typical for adenosine deaminase (ADA) deficiency.
High-resolution computed tomography (HRCT) and nuclear scanning
HRCT scans may uncover important lung abnormalities in patients with CVID and primary hypogammaglobulinemia. These include, but are not limited to, pulmonary fibrosis, bronchiectasis, parenchymal scarring, pleural thickening, and, less commonly, emphysema or parenchymal nodules.
HRCT scans are more sensitive than chest radiograph for detecting asymptomatic structural changes of airways and lung parenchyma that sometimes occur despite appropriate intravenous immunoglobulin (IVIG) therapy.
Imaging studies of the abdomen may show organomegaly. Splenomegaly may be observed in CVID in the absence of lymphoma or lymphoproliferative disease. Pathologic-appearing para-aortic and other abnormal abdominal lymph nodes may be stable findings in CVID; they should be monitored carefully and may require studies using other modalities (fluorodeoxyglucose positron emission tomography [FDG-PET] and/or biopsy) to rule out malignancy.
ADA levels should be measured in patients with SCID. The diagnosis of ADA deficiency is made by finding ADA levels less than 1% of the reference range. Cost-benefit analysis dictates that enzyme assays should be checked before genetic analysis. Also in the differential are mutations in purine nucleoside phosphorylase; this should be evaluated along with ADA levels. Tests can be done prenatally on amniotic fluid.
Absent or decreased Wiskott-Aldrich syndrome protein (WASP) can be determined by flow cytometry or western blotting. For Wiskott-Aldrich syndrome (WAS), sequence analysis determines 99% of mutations known to cause the disease entity.
Prenatal diagnosis of X-linked agammaglobulinemia (XLA), X-linked hyper-IgM syndrome (XHM), WAS, and ADA deficiency can be accomplished by restriction fragment length polymorphism (RFLP) using fetal blood, amniotic cells, or chorionic villus tissue.
The most consistent feature of individuals with XLA is the absence or extreme decrease in the number of B cells (CD19+ cells). The BTK gene contains the mutation.
Umbilical cord blood can be used in the prenatal diagnosis of some of these disorders. B cells are absent in XLA. T cells are absent in X-linked SCID. "Bald" lymphocytes found on scanning electron microscopy is diagnostic of WAS. Red blood cell ADA is decreased in fetuses with ADA deficiency.
Commercial laboratories are available for many of these tests. More information can be found at www.genetests.org
Lymph node biopsy is not a necessary diagnostic test in these disorders and can be complicated by poor healing and infection. However, it should be considered for rapidly enlarging lymph nodes to rule out infection or malignancy.
Rectal biopsy in CVID and IgA deficiency may show plasma cell and lymphoid cell infiltrate in rectal tissue. The presence of G lamblia or cryptosporidia can be documented via intestinal biopsy, which may show findings similar to sprue.
Thymus biopsy is indicated only in the presence of thymoma.
In XLA, lymph node biopsy reveals underdeveloped or rudimentary germinal centers. The same finding also can be documented in the tonsils, Peyer patches, and appendix.
In CVID, lymphoid follicles in lymph nodes, spleen, and gut are characterized by hyperplastic B-cell areas.
The thymus in patients with X-linked SCID resembles fetal thymus and is characterized by lobules of undifferentiated epithelial cells and depleted T-cell areas and, occasionally, both T-cell and B-cell areas.
In ADA deficiency, remnants of Hassall bodies can be seen in the thymus.
IgG replacement therapy is the treatment of choice for most primary immunodeficiency syndromes, including X-linked agammaglobulinemia (Bruton disease; XLA), common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), hyper-IgM, adenosine deaminase (ADA) deficiency, and Wiskott-Aldrich syndrome (WAS). IgG is usually routinely administered intravenously (IVIG) or subcutaneously (SCIG). IgG replacement is usually needed for at least 1 year after hematopoietic stem cell transplantation (HSCT) in patients with SCID.
Patients with IgG subclass deficiency should not be given IVIG unless they fail to produce antibodies to protein and polysaccharide antigens and they have significant morbidity due to infection that cannot be managed with antibiotics alone. In selective IgA deficiency, IVIG therapy is not indicated.
Effort should be focused on the treatment of infections, allergic reactions, autoimmune diseases, and gastrointestinal diseases. Aggressive and prolonged antibiotic therapy covering S pneumoniae and H influenza is indicated. Because of the high frequency of G lamblia infection in these patients, an empiric course of metronidazole may result in dramatic improvement of the diarrhea and, to a certain extent, of malabsorption syndrome.
The treatment of secondary hypogammaglobulinemia is directed at the underlying cause. Successful treatment of nephrotic syndrome and protein-losing enteropathy may result in improvement of Ig levels.
IVIG is not indicated for the treatment of lymphoproliferative disorders, unless Ig levels are low in association with recurrent infections or if IVIG is being used for autoimmune conditions such as immune thrombocytopenic purpura (ITP) or immune hemolytic anemia, which may accompany these disorders.
Live vaccines (eg, bacille Calmette-Guérin, polio, measles, rubella, mumps) should not be given to patients with T-cell disorders, XLA, or other severe B-cell disorders or to the family members of such patients. In patients with IgA deficiency, live vaccines are not an absolute contraindication if given intramuscularly.
High doses of IVIG or intrathecal Ig may be beneficial in patients with XLA who have enteroviral meningoencephalitis.
HSCT is the treatment of choice for patients with SCID and, if a matched donor is available, for a patient with ADA deficiency.
In patients with ADA deficiency who lack an HLA-identical sibling, enzyme replacement with polyethylene glycol-ADA (PEG-ADA) may be an effective alternative therapeutic agent.
Tumor necrosis factor (TNF) inhibitors have been used to treat granulomatous diseases in patients with CVID.
Gene therapy has been shown to be successful in reconstituting immune function in infants with X-linked SCID, but efficacy is less proven in older children and young adults. Gene therapy for ADA deficiency is most effective when patients receive myeloablative chemotherapy and are withdrawn from PEG-ADA beforehand. Case series of ADA-deficient patients receiving gene therapy have shown excellent results at 4-year follow-up.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. The standard treatment for hypogammaglobulinemia is IgG replacement, which may be given intravenously or subcutaneously.[9, 10, 20] IgG preparations are approved by the US Food and Drug Administration (FDA) for treatment of primary immunodeficiency disease (primary humoral immunodeficiency) and a few additional indications, but considerable amounts of intravenous immunoglobulins (IVIG) are used "off label" for other conditions.[9, 20]
As reviewed by the American Academy of Allergy, Asthma, and Immunology, the benefit of IgG treatment for these primary immune deficiencies is based on category IIb evidence (13). IVIG is approved for only 2 secondary immune deficiencies: B-cell chronic lymphocytic leukemia (B-CLL) and pediatric HIV. The use of IVIG for primary immune defects with normogammaglobulinemia and impaired specific antibody production is based on category III evidence only.
The usual IVIG dose is 0.4-0.6 g/kg every 3-4 weeks, titrating the dose and interval between infusions to achieve a trough IgG level greater than 500 mg/dL. Usual total monthly doses of subcutaneous IgG (SCIG) are in the same range, given as 100-200 mg/kg/wk. Some practitioners target trough levels 300 mg/dL higher than pretreatment levels, and trough levels >800 mg/dL may improve pulmonary outcomes. Some centers administer a loading dose of 1g/kg if the patient is agammaglobulinemic.[9, 10, 20]
Gammaglobulin may also be given intramuscularly or subcutaneously. The latter format is useful when allergic reactions limit the dose or rate, but it is becoming increasingly popular even when these problems are not present. SCIG can be given at home by parents or by patients themselves, usually requiring several hours of infusion. Intramuscular gammaglobulin injections were the standard of care before IVIG became readily available and are still useful in certain patients because of the simplicity of administration and fewer reactions. However, local injection site pain can be significant, and the doses that can be given this way are limited.
Up to 44% of patients report adverse reactions to IVIG. These most commonly respond to decreasing the rate of the Ig infusion. Usually, the IVIG-associated reactions are infusion-related and include back pain, abdominal aching, nausea, rhinitis, asthma, chills, low-grade fever, myalgias, and headaches. Renal failure is a less common but serious adverse reaction that was predominately caused by sucrose-containing lyophilized IgG preparations that are no longer available in the United States. Infusion rate reduction, systemic steroids, histamine blockers, and antipyretics or nonsteroidal anti-inflammatory drugs (NSAIDs) can help treat or prevent the reactions.
Although the incidence of reactions is highest during the first infusion, they may occur in repeat infusions of the same product. Although anti-IgA antibodies can be associated with increased reactions, most patients (regardless of anti-IgA antibody status) tolerate IVIG that is not depleted of IgA (low-IgA products should be selected for treatment in patients who cannot tolerate IVIG that is not depleted of IgA). Thrombosis, myocardial infarction, hemolytic anemia, hyperviscosity syndrome, and aseptic meningitis are uncommon but reported adverse events.
Regular follow-up of the following parameters is necessary:
Growth and development should be monitored in children.
Chest radiograph and, if pulmonary abnormalities are suggested, high-resolution CT (HRCT) should be performed and repeated annually or as appropriate.
Pulmonary function tests should be performed and, if abnormal, monitored annually.
Immunoglobulin trough levels greater than or equal to 500 mg/dL are considered satisfactory, but levels greater than 600 mg/dL may be beneficial in patients with chronic lung or sinus disease. Doses and treatment intervals should be titrated in individual patients to determine the level needed to prevent recurrent infection without excessive use of this expensive medication.
Liver function tests should be performed and, if abnormalities are identified, nucleic acid tests should be used to determine if a potentially blood-borne infection (such as viral hepatitis) is present. Repeated results that suggest biliary disease may require follow-up with imaging studies of the liver and/or biliary tree to rule out malignancies or sclerosing cholangitis (the latter is seen in X-linked hyper-IgM syndrome [XHM]).
Lymphocyte surface marker analysis and serum immunoelectrophoresis may be indicated at routine intervals to screen for lymphoma and other malignancies.
In most cases, intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) therapy can be given at home once safety has been established in the office/clinic. Home care nursing is usually required for IVIG therapy but may be unnecessary with SCIG.
Prophylactic and/or rotating full-treatment dose antibiotics may be useful in patients with chronic otitis, sinusitis, or chronic/recurrent bronchitis with bronchiectasis.
Bronchodilators, inhaled corticosteroids, inhaled anticholinergics, or a combination thereof may be indicated for patients whose lung disease includes components of bronchospasm, or bronchorrhea.
Spruelike syndrome with malabsorption is observed in 10% of patients with common variable immunodeficiency (CVID). Upon small bowel biopsy, this syndrome resembles gluten-sensitive enteropathy, except for the absence of plasma cells. Infectious enteritis can be mistaken for ulcerative colitis or Crohn disease; both seem to occur with increased frequency in patients with CVID. Children with CVID frequently have lymphoid hyperplasia in the intestines, which may be comprised of plasmacytoid cells of B-cell lineage.
Vaccine-associated poliomyelitis may occur in patients with X-linked agammaglobulinemia (XLA) who receive the attenuated live poliovirus vaccine (no longer commonly used for infants in the United States).
Persistent enteroviral infection and chronic sinusitis remain the major complications of patients with XLA.
Viral encephalitis caused by, in decreasing order, enterovirus, coxsackievirus, measles, and papovavirus are potentially rare and devastating complications of hypogammaglobulinemia.
Hearing loss due to chronic otitis media or meningoencephalitis may affect as many as one third of patients with XLA and may also affect patients with CVID and specific antibody deficiency syndromes.
Bronchiectasis and cor pulmonale may complicate chronic or recurrent lower respiratory infections.
The most common disorders are Coombs-positive hemolytic anemia and idiopathic thrombocytopenic purpura.
Neutropenia is observed less frequently. Nonimmune neutropenia is seen in young boys with XLA, and drug-induced neutropenia should be considered in other patients.
Pernicious anemia (due to autoimmunity) occurs in 10% of patients with CVID and is characterized by a younger age of onset and an absence of detectable antiparietal cell antibodies. Vitamin B12 deficiency should be considered in patients with CVID who do not have evidence of blood loss or iron deficiency.
Other less common autoimmune disorders have been reported, including thyroid diseases, Addison disease, diabetes mellitus, biliary cirrhosis, alopecia totalis, rheumatoid arthritis, systemic lupus erythematosus, polymyositis, sicca syndrome, and Guillain-Barré syndrome.
The risk of cancer in patients with CVID is 5 times higher than in matched controls. A 47-fold increase in gastric cancer and a 30-fold increase in lymphoma have been reported. The role of chronic infection with Helicobacter and other enteric pathogens in these cancers is suspected. Benign lymphoproliferative disorders are much more common, affecting up to 30% of patients, and manifest as splenomegaly, with or without diffuse lymphadenopathy. They are distinguished from lymphomas by the presence of a mixture of B and T lymphocytes and by the absence of clonal B-cell and T-cell receptor rearrangement.
A noncaseating granulomatous disease involving the lungs, lymph nodes, skin, bone marrow, and liver has been described in patients with CVID. This entity should be differentiated from mycobacterial and fungal infections. In the small subset of patients with aggressive disease, corticosteroids and tumor necrosis factor (TNF) inhibitors are the treatments of choice. Granulomatous disease in the lungs is often associated with hilar, retroperitoneal, or abdominal lymphadenopathy.
Anaphylactic reactions can occur in rare instances when patients with IgA deficiency receive blood products containing IgA.
The risk of graft versus host disease (GVHD) is high in patients with SCID because of their inability to reject foreign antigens. Infants with SCID may present with GVHD before transplantation, due to engraftment with maternal lymphocytes before birth.
A dermatomyositis-like syndrome, a rare complication of Bruton disease, is a constellation of edema of subcutaneous tissue, rash, and muscle weakness. Chronic enteroviral meningoencephalitis also can be observed with this disorder.
Complications related to immunoglobulin therapy
Nonanaphylactic reactions: The most common adverse reactions to IVIG are back and abdominal pain, nausea, vomiting, chills, fever, and myalgias. The infusion should be discontinued until the symptoms subside; then, it should be restarted at a slower rate after administration of premedication (eg, oral or intravenous hydration, antipyretics, antiemetics)
Local reactions to SCIG are common but are rarely persistent or serious.
Anaphylactic reactions: These are rare. They are IgE-mediated in patients with IgA deficiency and occur from seconds to hours after the infusion is started. IgG anti-IgA antibodies may be responsible for anaphylactoid reactions due to complement activation. Typical symptoms consist of flushing, facial swelling, dyspnea, and hypotension. The infusion should be stopped, and the patient should receive epinephrine, glucocorticoids, and antihistamines. Pure cutaneous reactions such as flushing and urticaria can be treated as nonanaphylactic reactions, with supportive and symptomatic therapy as needed.
Prognosis has improved significantly since the introduction of IVIG therapy to routine practice.
Mortality due to overwhelming infections remains a major risk for these patients, although chronic progressive morbidity is more likely.
Chronic lung and liver diseases result in significant morbidity and mortality.
The risk of malignancy, especially lymphomas involving mucosal-associated lymphoid tissue, must be kept in mind.
For those who survive long enough, autoimmune diseases and cancers become a serious threat because the incidence of these diseases is several-fold higher in these patients than in matched controls.
SCID is a true pediatric emergency that may not be apparent on the newborn physical examination. Patients do not survive beyond childhood unless a definitive treatment is performed. However, if hematopoietic stem cell transplantation is performed a bone within the first 3 months of life, the chance of survival is approximately 93%.
Robert Y Lin, MD, Professor, Department of Medicine, New York Medical College; Chief, Allergy and Immunology, and Director of Utilization Review, Department Medicine, New York Downtown Hospital
Disclosure: Nothing to disclose.
Amit J Shah, MD, Allergist/Immunologist, Asthma and Allergy Clinic of Utah, Salt Lake City, UT
Disclosure: Nothing to disclose.
Jenny Shliozberg, MD, Associate Clinical Professor, Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine; Consulting Staff, Department of Pediatrics, Montefiore Hospital Medical Center and Albert Einstein College of Medicine; Director of Pediatric Allergy and Immunization Clinic, Children's Hospital at Montefiore Medical Center
Disclosure: Nothing to disclose.
Melvin Berger, MD, PhD, Adjunct Professor of Pediatrics and Pathology, Case Western Reserve University; Senior Medical Director, Clinical Research and Development, CSL Behring, LLC
Disclosure: CSL Behring Salary Employment; CSL Behring Ownership interest Employment; America's Health insurance plans Consulting fee Subject Matter Expert For Clinical Immunization Safety Assessment Network acvtivity of CDC
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Michael R Simon, MD, MA, Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Professor, Department of Internal Medicine, Oakland University William Beaumont University School of Medicine; Adjunct Staff, Division of Allergy and Immunology, Department of Internal Medicine, William Beaumont Hospital
Disclosure: Secretory IgA, Inc. Ownership interest Management position; siRNAx, Inc. Ownership interest Management position
Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy
Disclosure: Teva Honoraria Speaking and teaching; Meda Honoraria Speaking and teaching; genentech Honoraria Speaking and teaching; sunovian Consulting fee Consulting
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.