The term hypogammaglobulinemia refers to low immunoglobulin G (IgG), which may be mild or severe, and etiology may be characterized as primary (from low or absent B-cell function) or secondary (due to excessive loss or rapid catabolism). Patients with low IgG may be asymptomatic or they may have a number of associated symptoms, especially infections, depending on the etiology of the low IgG. See Workup for a set of questions that will assist in categorizing the hypogammaglobulinemia as primary or secondary.
This article primarily elaborates on hypogammaglobulinemia that is caused by low or absent B-cell production, ie, primary hypogammaglobulinemia.
Signs and symptoms
Patients with secondary immune deficiency from GI and renal losses do not usually present with infection, but with symptoms of their primary disease.
Patients with mild primary hypogammaglobulinemia (slightly low Immunoglobulin) may be asymptomatic, but those with more severe primary hypogammaglobulinemia usually present with a history of recurrent infections. A detailed clinical history should emphasize the following items associated with immune deficiency:
Age of onset
Family history for immune deficiency
Infection history: Number of infections, site of infection, organisms responsible for infection, unusual infections and unusual complications of usual infection, essentially questions to elicit a history of immune deficiency
Autoimmune and collagen vascular disease history that may occur from immune dysregulation
Physical findings will vary by etiology, but primary hypogammaglobulinemia (associated with a primary immune deficiency) may include the following:
Growth retardation in children
Abnormalities of lymphoid tissue and organs (eg, a paucity of tonsillar tissue, adenoids, and peripheral lymph nodes)
Developmental abnormalities (eg, skeleton or chest wall anomalies, facial anomalies)
Abnormalities of skin and mucous membranes (eg, scars, rash, or livedo reticularis)
Ear, nose, and throat abnormalities (eg, tympanic membrane perforation, purulent nasal discharge, cobblestone pattern of pharyngeal mucosa, and nasal exudate)
Pulmonary abnormalities suggestive of recurrent infections (eg, rales, rhonchi, and wheezing may be symptoms of bronchiectasis, fibrosis, or other chronic lung disease)
Cardiovascular abnormalities associated with DiGeorge or CHARGE syndrome
Physical exam findings in secondary hypogammaglobulinemia will vary by etiology.
See Clinical Presentation for more detail.
Diagnosis
Laboratory studies that may be helpful in determining cause of hypogammaglobulinemia include the following:
Serum immunoglobulin levels (IgA, IgG, and IgM)
Complete blood count with differential
Antibody response to recall antigens
Isohemagglutinins (especially useful if patient already received passive IV or SC Immunoglobulin as treatment because it evaluates ability to make IgM antibodies)
Peripheral blood lymphocyte immunophenotyping (CD19+ B cells, CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD3-56+16+ NK cells)
Evaluation of cellular immunity (mitogen and antigen proliferation assays)
Urinalysis to evaluate for protein losses
Inflammatory markers
Imaging studies that may be useful include the following:
Chest radiography
High-resolution computed tomography (HRCT) to evaluate for bronchiectasis and other lung disease/infection if suspected
The following tests may be considered as circumstances warrant:
Genetic testing as indicated by abnormalities on immunology tests
Microarray for DiGeorge (primarily T-cell disorder, but T-cell disorders will lead to B-cell dysfunction if severe) and evaluation for genetic variants of SCID, CVID, and other immune deficiencies if warranted
HIV testing (although untreated HIV is classically associated with hypergammaglobulinemia, late-stage HIV (AIDS) may be associated with loss of immunoglobulin)
The following biopsy procedures may also be considered:
Lymph node biopsy (for rapidly enlarging lymph nodes to rule out infection or malignancy)
Thymus biopsy (indicated only for thymoma)
See Workup for more detail.
Management
In cases of slightly low immunoglobulin (IgG) where antibody production is intact, watchful waiting is encouraged. Infants with transient hypogammaglobulinemia often have resolution of this finding without intervention, and they do retain the ability to make antibody. Some individuals who are not infants will have low immunoglobulin without disruption of ability to produce antibody, and require no intervention. Watchful waiting is advised, however, to be certain that CVID is not developing. This will only be apparent with serial IgG levels.
Replacement therapy with immunoglobulin G (IgG), administered intravenously (IVIG) or subcutaneously (SCIG), is the treatment of choice for most primary immunodeficiency syndromes where very low or absent immunoglobulin is a feature.[1] These include the following:
X-linked agammaglobulinemia (Bruton disease; XLA)
Severe combined immunodeficiency (SCID) prior to stem cell or bone marrow transplantation
Common variable immune deficiency (CVID)
Hyper-IgM
ADA deficiency
Wiskott-Aldrich syndrome (WAS)
Syndromes associated with low immunoglobulin or poor antibody production
Sometimes specific antibody deficiency (ie, some patients with specific antibody deficiency will have a normal IgG level)
If poor T-cell function is also a part of the immune deficiency (ie, severe combined immune deficiency or combined immune deficiency), stem cell transplant or bone marrow transplant may be the definitive treatment, and may replace B cell function so that IgG replacement is no longer necessary.[2, 3, 4]
Treatment of secondary hypogammaglobulinemia is directed at the underlying cause.
IVIG is not indicated for lymphoproliferative disorders unless immunoglobulin levels are low in association with recurrent infections or if IVIG is being used for autoimmune conditions that may accompany these disorders
If IgG is being lost through the gut or kidney, replacement of IgG will not be effective
The term hypogammaglobulinemia refers to low immunoglobulin G (IgG), which may be mild or severe, and etiology may be characterized as primary (from low or absent B cell function) or secondary (due to excessive loss or rapid catabolism). Patients with low IgG may be asymptomatic, especially if the IgG is mildly below normal, or they may have a number of associated symtpms depending on the etiology of the low IgG.
Hypogammaglobulinemia has varied causes and manifestations. It can be associated with a primary immune deficiency, be part of a multisystemic syndrome, or be secondary to other disorders. The common clinical feature of severe hypogammaglobulinemia is a predisposition toward infections that require antibody responses for irradication. These include but are not limited to Streptococcus pneumoniae and Haemophilus influenzae infections, which frequently involve the respiratory tract.
While primary immunodeficiencies causing hypogammaglobulinemia are relatively uncommon, the demand for gammaglobulin treatment has grown and placed demands on the limited supply of this treatment. Therefore, an awareness of the appropriate diagnostic and therapeutic approaches to hypogammaglobulinemia is important.
In infants, hypogammaglobulinemia may be transient because of slow development of B-cell function, and is usually asymptomatic.[5]
Disorders of the immune system that can result in hypogammaglobulinemia can involve B cells, T cells, or both because protein antigens require T-cell recognition and T-cell help via cytokine signaling in order for B cells to produce antibodies. Some polysaccharide antigens do not require T-cell help for antibody production.[6]
The information in this article is not meant to be a comprehensive review of primary immune deficiency, 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.
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.
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 with the assistance of T cells and this is why vaccines against polysaccharide antigens are designed to utlize a protein conjugate to engage T-cell help. 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 normally begins endogenous production of IgG. If endogenous production does not happen because of B-cell deficiency, infections will occur.[6, 7]
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 B cells that have matured into plasma cells.
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).[8]
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.[9]
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.
Normal 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 usual 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.
Renal loss of whole immunoglobulins occurs in nephrotic syndrome, in which albumin loss may be accompanied by immunoglobulin loss. Other types of acquired or secondary hypogammaglobulinemia include results of medications either intentional or as side effects (eg rituximab or corticosteroids versus phenytoin), gastrointestinal immunoglobulin loss, B-cell–related malignancies, and severe burns. Gastrointestinal loss occurs in protein-losing enteropathies and intestinal lymphangiectasia. Increased catabolism occurs in various diseases, including B-cell lineage malignancies and severe burns, but also in dystrophic myotonia.
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 two disorders is estimated to be 1 case in 700 persons and 1 case in 5000–10,000 persons of European ancestry, respectively. Selective IgM deficiency is a rare disorder. The incidence of agammaglobulinemia is approximately 1 in 200,000, and the incidence of severe combined immune deficiency (SCID) is approximately 1 in 50,000.[10, 11]
Mortality/morbidity
Morbidity and mortality will, of course, vary by the etiology of the hypogammaglobulinemia.
Patients with immune deficiencies resulting in hypogammaglobulinemia experience an increased incidence of a large spectrum of infections starting at an early age. Early identification and replacement of Ig will greatly alter the incidence of infection; for example,15% of untreated patients with X-linked agammaglobulinemia (XLA) die of infectious complications by age 20 years, but most have relatively normal life spans if they are diagnosed and begin immunoglobulin replacement therapy in early childhood, before chronic lung infection begins.[8]
In some types of CVID, which is a variable disorder with multiple genetic etiologies, patients are prone not only to infection but also immune dysregulation with increased risk of autoimmune disorders and cancer.[12, 13, 14]
Recurrent infections may ultimately lead to significant end-organ damage, particularly involving the respiratory system.
Patients with certain inherited disorders may not survive infancy or early childhood, and growth may be affected for those who survive. Patients with SCID usually 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.[15, 16] Most patients with Wiskott-Aldrich syndrome (WAS) die by the second decade of life if they do not 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 require care at highly specialized centers.
Demographics
In children, primary immunodeficiencies are more common in boys than in girls (male-to-female ratio of approximately 5:1). In adults, primary immunodeficiencies are diagnosed almost equally in both sexes (male-to-female ratio of approximately 1:1.4).
XLA, X-linked hyper-IgM syndrome, X-linked SCID, and WAS are X-linked disorders for which females are carriers and only males are affected. However, WAS may occur in female carriers if skewed inactivation of the X chromosome occurs, resulting in an active X chromosome carrying the Wiskott-Aldrich mutation.
CVID and IgA deficiency affect both sexes equally. Symptoms in XLA typically begin around 6 months of age, when the concentrations of maternal antibodies decline. However, this may vary considerably, depending in large part on the baby's exposure to other children carrying infectious organisms. Unfortunately, the diagnosis is often missed or delayed until significant morbidity has occurred. Some patients with atypical XLA mutations and others with autosomal hypogammaglobulinemia do not develop recurrent infections and laboratory abnormalities until adulthood and may be misdiagnosed with CVID or selective antibody deficiency.
Infections in SCID that is not detected by newborn screening, including severe candidiasis, pneumocystis jiroveci pneumonia, and cryposporidium, usually begin in the first months of life.
The symptoms of hyper-IgM syndromes usually begin during the first 2 years of life. Chronic cryptosporidia infection may be particularly problematic in X-linked hyper-IgM.
Patients with WAS start experiencing recurrent bacterial infections during the first year of life.
Patients with reticular dysgenesis have loss of all leukocytes 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 and more are being diagnosed early because of newborn screening initiatives.[17] Because the failure of the immune system is gradual, some cases are not diagnosed until later childhood.
CVID has a variable age of onset, usually occurring by the third decade of life. However, on average, CVID patients experience increased infections and other symptoms for 10 years before their diagnosis is recognized.[13, 14]
Ig deficiency with thymoma (Good syndrome) affects adults aged 40–70 years.
Prognosis depends on etiology of hypogammaglobulinemia.
Prognosis for hypogammaglobulinemia secondary to excessive loss is dependent on treatment of causative disease.
Prognosis for hypogammaglobulinemia due to primary immune deficiency has improved significantly since the introduction of IVIG or SCIG therapy.
Mortality due to overwhelming infections remains a major risk for patients with, 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.
Autoimmune disease and cancer incidence is several-fold higher in immune deficiency patients than in matched controls.
Severe combined immunodeficiency (SCID) is a true pediatric emergency that may not be apparent on the newborn physical examination. Newborn screening detects the vast majority of these patients so that survival is increased significantly because treatment with prophylactic immunoglobulin therapy and antibiotics followed by hematopoietic stem cell transplantation or gene therapy can be performed within the first 3 months of life before any infection occurs. Without intervention, patients do not survive beyond early childhood.
Educational information should emphasize treatment of causative conditions leading to hypogammaglobulinemia, or watchful waiting if no treatment is called for (eg transient hypogammaglobulinemia). If the hypogammaglobulinemia is secondary to another disease process, the patient may require information about why IVIG/SCIG is probably not indicated for renal and GI losses of IgG. If the hypogammaglobulinemia is secondary to a primary immune deficiency, the educational process will revolve around treatments and prophylaxis against infections.
The term hypogammaglobulinemia refers to low immunoglobulin G (IgG), which may be mild or severe, and etiology may be characterized as primary (from low or absent B cell function) or secondary (due to excessive loss or rapid catabolism). Patients with low IgG may be asymptomatic or they may have a number of associated symptoms, especially infections, depending on the etiology of the low IgG.
Causes of hypogammaglobulinemia considered primary include inability to produce immunoglobulin or slow production of immunoglubulin.[10] The defect may be in the B cells or T cells, which are necessary (T-cell help) for B-cell production of most immunoglobulin, including:
Transient hypogammaglobulinemia of infancy (sometimes considered a primary immune deficiency, but may be benign)
Causes of secondary hypogammaglobulinemia occur from rapid loss or excessive catabolism of IgG including:
Gastrointestinal loss from protein losing enteropathies or intestinal lymphangiectasia
Renal losses especially nephrotic syndromes
Severe burns
Signs and symptoms
Patients with mild hypogammaglobulinemia (slightly low Immunoglobulin) may be asymptomatic, but those with more severe hypogammaglobulinemia usually present with a history of recurrent infections. A detailed clinical history should emphasize the following:
Reason for lab draw that defined the abnormality
Medications
Symptoms (especially infections)
Age of onset
Family history
Site of infections
Type of microorganisms involved in infections
Unusual infections or unusual complications of infections
Recurrent infections and/or prolonged
Gastrointestinal symptoms
Musculoskeletal symptoms
Autoimmune and collagen vascular diseases
Patients with hypogammaglobulinemia from GI or renal disease will present with signs and symptoms of their primary disease. If the hypogammaglobulinemia is secondary to a primary immune deficiency or another cause of decreased production the patients usually present with a history of recurrent infections, failure to thrive, autoimmune disease, and more rarely with malignancies (especially leukemias or lymphomas). A detailed clinical history should emphasize the following to identify immune deficiency:
Family history
A family history of frequent infections, persons receiving immunoglobulin, or infants who died at an early age due to infection are all suggestive of immune deficiency.
Age of onset
Transient hypogammaglobulinemia of infancy, as its name implies, represents a delay in the maturation of the full range of antibody responses, is a disorder or benign variant in infancy, and usually resolves by a few years of age.
Onset of hypogammaglobulinemia during early childhood suggests an inherited disorder of B cell/and or T cell maturation, specifically a primary immune defciency.
Acquired hypogammaglobulinemias may start at any age, depending on the underlying cause, and some primary immune deficiencies (eg CVID) present after childhood).
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.[8]
Diffuse lymphoid hyperplasia may accompany CVID and some hyper-IgM syndromes, and splenomegaly with or without hypersplenism occurs in 25% of patients with CVID. Lymph node biopsy from patients with CVID may show the absence of follicles and germinal centers with a relative paucity of plasma cells, or reactive hyperplasia may be present. The stomach and/or intestines may have hypertrophic folds and/or lymphoid hyperplasia in CVID.
Developmental abnormalities
Skeletal and chest wall abnormalities affecting the vertebral bodies and the chondrocostal junctions occur in patients with adenosine deaminase deficiency.
Skin and mucous membranes
Severe eczematoid rash is typical of WAS.
Livedo reticularis with muscle weakness or a dermatomyositis-like syndrome may present with XLA or CVID.
A lupuslike rash may occur with CVID.
Ear, nose, and throat
Tympanic membrane perforation or scarring, with hearing loss, can occur because of recurrent otitis media. Purulent nasal discharge, a cobblestone pattern of pharyngeal mucosa, and nasal exudate usually are present, consistent with chronic sinusitis, which is one of the most common findings in these patients.
Note the presence or absence of tonsillar tissue.
Pulmonary
Recurrent bronchitis and pneumonias can lead to bronchiectasis and lung fibrosis.
Rales, rhonchi, and wheezing can be observed on lung examination in such patients.
Digital clubbing may result from chronic obstructive pulmonary disease (COPD).
Cardiovascular system
Chronic respiratory insufficiency can result in pulmonary hypertension and, eventually, right-sided heart failure.
Neurologic
Paralytic poliomyelitis may occur in patients with antibody deficiencies following vaccination with live attenuated poliovirus vaccine, although live polio vaccinations are no longer used in the United States.[18]
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. 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 from birth.
Mutations in the Bruton tyrosine kinase (BTK) gene and protein have been implicated in this entity.[10]
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.[8]
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
Hyper-IgM syndromse include deficiencies of CD40 ligand (CD154), activation-induced cytidine deaminase [AID], and uracil-nucleoside-glycosylase [UNG]). They are 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.[19]
IgG subclass deficiency
This syndrome is defined as one or more IgG subclasses at 2 standard deviations below the mean, with normal total IgG and IgM levels. IgA levels may also be low.
Whether this entity should be categorized under the CVID heading is controversial. By definition, 2.3% of the "normal" population fits such a classification. A few case series report these patients having recurrent sinopulmonary infections and environmental allergies.
No specific genetic cause is identified
Specific antibody deficiency (SAD)
Specific antibody deficiency (SAD), also known as specific polysaccharide antibody deficiency (SPAD), may be associated with normal IgG levels or hypogammaglobulinemia
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. 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.[20]
Common variable immunodeficiency (CVID)
CVID is present in 1 in 5,000–7,000 people. CVID is not one disease but a variable group of disorders leading to immune deficiency and immune dysregulation. 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 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, including splenomegaly, generalized lymphadenopathy, or intestinal lymphoid hyperplasia. These patients are at increased risk for developing non-Hodgkin lymphoma and other malignancies.
This diagnosis should not be assigned to patients younger than 4 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.
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% 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 and other immune suppression to control autoimmune manifestations, and splenectomy is sometimes necessary to stop autoimmune hemolysis.[12, 13, 14]
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. Many infants with transient hypogammaglobulinemia are asymptomatic, but the low IgG may leave 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.[5]
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, watchful waiting is sufficient in these infants. If IgG therapy is started it should be temporarily stopped every 3–6 months to reassess 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.[21]
Combined T-cell and B-cell disorders
A few examples are given here. A more extensive review can be found in T-cell disorders.
Severe combined immunodeficiency (SCID)
SCID is now most often detected on newborn screening (NBS). As its name implies, SCID is the most severe of the pediatric immunodeficiencies. Treatment with stem cell or bone marrow transplant before significant infection occurs improves morbidity and mortality.[15, 22]
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. 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.[23]
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.
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.
IgG replacement is appropriate for the treatment of the immunodeficiency aspect of this syndrome and some patients may benefit from antibiotic prophylaxis. A multidisciplinary approach to the patient as a whole should be undertaken to address the multisystem nature of this disease.[10, 11]
Secondary or acquired diseases
Nephrotic syndrome
Decreased levels of IgG can appear with normal levels of IgA and IgM in the nephrotic syndrome.
Protein-losing enteropathy
Intestinal lymphangiectasia, which is sometimes considered as a subset of protein-losing enteropathies, frequently causes not only loss of protein, but also of B-cells, leading to lymphopenia. This occurs because of intestinal lymphatic blockade with resulting leakage of lymphatic fluid and cellular components into the lumen.
Both nephrotic syndrome and protein-losing enteropathies manifest with hypoalbuminemia and, usually, edema. IgG levels are affected more than IgM or IgA levels in protein-losing enteropathies. However, levels of IgG, IgM, and IgA, and the cells that produce them, may all be reduced in severe protein-losing enteropathy.Specific antibody response to vaccines is usually normal in these patients despite low levels of immunoglobulin particularly IgG and IgA.
Catabolic disorders
Increased catabolism occurs in various diseases, including the B-cell lineage malignancies, severe burns, and myotonic dystrophy.
Immunosuppressive therapy
Immunosuppressant medication can cause hypogammaglobulinemia, especially in the setting of solid organ transplantation. Long-term corticosteroid treatment can also result in hypogammaglobulinemia, which may, rarely, be symptomatic. Patients with asthma and with hypogammaglobulinemia secondary to corticosteroid use retain specific antibody responses and, thus, are not necessarily candidates for immunoglobulin replacement therapy. Patients presenting with sinusitis and/or bronchitis with secondary bronchospasm, however, may have CVID or other forms of antibody deficiency that will respond to IgG replacement. Patients who take daily doses of ≥ 12.5 mg prednisone for 1 year or more are more likely to have hypogammaglobulinemia.
Immunosuppressants combined with corticosteroids may create an even greater propensity toward hypogammaglobulinemia. Such treatments are commonly used in patients with autoimmune and neoplastic diseases. Rituximab (anti-CD20) treatment in neoplastic and/or autoimmune disease also may be associated with hypogammaglobulinemia. Chemotherapy, autologous stem cell transplantation, or both may contribute to the hypogammaglobulinemia.
Although malnutrition and radiation have been purported to cause secondary hypogammaglobulinemia, the literature supporting this association is weak. For example, studies on malnourished African children showed that cellular immunity was much more impaired than humoral immunity. Total lymphoid irradiation used in the past for rheumatoid arthritis did not decrease rheumatoid factor levels, suggesting that nonmyeloablative irradiation has little effect on immunoglobulin levels. Thyrotoxicosis is not associated with hypogammaglobulinemia.
Lymphoproliferative malignancies
Chronic lymphocytic leukemia: B-cell chronic lymphocytic leukemia (B-CLL) is often associated with hypogammaglobulinemia and infections. 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.[24]
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.
Infections (especially sinopulmonary and GI) are the primary consequence of poor antibody production from hypogammaglobulinemia.
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).
Viral encephalitis caused by, in decreasing order, enterovirus, coxsackievirus, measles, and papovavirus are potentially rare and devastating complications of hypogammaglobulinemia.
Hearing loss due to chronic otitis media or meningoencephalitis may affect as many as one third of patients with XLA and may also affect patients with CVID and specific antibody deficiency syndromes.
Bronchiectasis and cor pulmonale may complicate chronic or recurrent lower respiratory infections.
Autoimmune diseases
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 common variable immunodeficiency (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.
Crohn's and Crohn's like IBD are more common in CVID.[12, 13, 14, 25]
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 some 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.[26]
Anaphylactic reactions have been reported to occur in rare instances when patients with IgA deficiency receive blood products containing IgA.
Complications related to immunoglobulin therapy
The most common adverse reactions to IVIG are nonanaphylactic reactions such as 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 subcutaneous immune globulin (SCIG) are common but are rarely persistent or serious.[1]
The following questions will assist in categorizing the hypogammaglobulinemia as primary or secondary.
What was the age of symptom onset? Onset in infancy is usually indicative of a primary cause. As placentally transferred maternal antibody wanes (4–6 months of age), an inability of B lymphocytes (B cells) to make immunoglobulin may result in hypogammaglobulinemia. Infants with agammaglobulinemia will present at this time. Infants with severe combined immune deficiency (SCID) may present with infection even earlier because they have a lack of T-cell function as well. B cells do not function without T-cell help in most cases, and immunoglobulin in SCID or combined immune deficiency (CID) patients will also be low as maternal antibody wanes. A lag in development of ability to make immunoglobulin and antibody (transient hypogammaglobulinemia), which is often relatively benign, may likewise be discovered as maternal antibody wanes. Transient hypogammaglobulinemia, as the name implies, improves with age. Older age at onset of hypogammaglobulinemia may still be associated with a primary immune deficiency, especially common variable immune deficiency (CVID), which usually presents in the second or third decade of life.[27, 10, 11]
Are there frequent infections or other indications of immune deficiency? Are there unusual infections, unusual complications of unusual infections, autoimmune disease, or malignancies? These are all signs of immune deficiency and/or immune dysregulation and would indicate primary hypogammaglobulinemia.[27, 11]
Medications? Some medications, such as steroids, rituxin (anti–B-cell monoclonal), and other immune suppressive or chemotherapy agents, may result in hypogammaglobulinemia. Some medications such as carbamazepine, valproic acid, and other antiepileptics may cause hypogammaglbulinemia as a side effect.[28, 29]
Are there signs and symptoms of renal or gastrointestinal (GI) losses? Passive loss of immunoglobulins requires treatment of the primary disease.
Causes of hypogammaglobulinemia considered primary include inability to produce immunoglobulin or slow production of immunoglubulin.[10] The defect may be in the B cells or T cells, which are necessary (T-cell help) for B-cell production of most immunoglobulin, including:
Transient hypogammaglobulinemia of infancy (sometimes considered a primary immune deficiency, but may be benign)
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. 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.
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.[10, 13]
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 increase is considered adequate in studies, but a protective level may also be considered adequate). Vaccine-induced antibodies should be determined 4–8 weeks after pneumococcal immunization.
Isohemagglutinins
IgM antibodies to A and/or B blood group antigens may be useful to check ability to make antibodies in someone who has received passive IgG. Antibodies to blood group antigens A would not be expected to be present if the patient's blood group is A, or to B if the blood group is B. AB group would make antibodies to neither A nor B. These antibodies normally develop in the first year of life in response to ingestion of cross-reacting animal antigens in food.
The production of recall 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
This is usually evaluated in blood by mitogen and antigen stimulation assays.
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.[30]
Renal studies
Renal disease in which protein loss causes hypogammaglobulinemia is easily diagnosed by quantitation of the total 24-hour urinary protein excretion.
Gastrointestinal studies
Protein-losing enteropathy that causes hypogammaglobulinemia may be more difficult to diagnose. Increased alpha1-antitrypsin (which is not present in normal diet) loss in the stool can be quantified in a 24-hour clearance procedure. Alternatively, a nuclear scan using technetium 99m dextran can be used to diagnose and localize protein-losing enteropathy.
Intestinal lymphangiectasia, which is sometimes considered a subset of protein-losing enteropathies, manifests not only with protein loss but also with lymphopenia. This occurs because of intestinal lymphatic blockade with resulting leakage of lymphatic fluid and cellular components into the lumen. Imaging and endoscopy are useful in diagnosing intestinal lymphangiectasia. However, this is often a "patchy lesion," and the diagnosis may be difficult.
In many patients with common variable immunodeficiency (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 severe combined immunodeficiency (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.
Adenosine deaminase (ADA) levels should be measured in patients with severe combined immunodeficiency (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[2]
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 common variable immunodeficiency (CVID) and IgA deficiency may show plasma cell and lymphoid cell infiltrate in rectal tissue.
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 severe combined immunodeficiency (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.[10]
Six distinct phenotypes of primary immunodeficiencies (PI) disease for which immunoglobulin replacement is or may be indicated include: (1) agammaglobulinemia due to absence of B cells; (2) hypogammaglobulinemia with poor antibody function; (3) normal immunoglobulins with poor antibody function; (4) hypogammaglobulinemia with normal antibody function; (5) isolated IgG subclass deficiency with recurrent infections; and (6) recurrent infections due to a complex immune mechanism related to a genetically defined PI disease. Recommendations are based on evidence categories ranging from quasi-experimental studies (IIb) to expert opinion.The list of PI diseases to be treated with immunoglobulins is likely to change in the future with better diagnosis and characterization of the diseases.
The goals of immunoglobulin (Ig) replacement therapy (IgRT) for patients with primary immunodeficiency is to provide adequate replacement immunoglobulins to minimize potentially fatal infections and prevent complications associated with the disease and improve quality of life. A brief overview of benefits of IgRT is in some of the phenotype of PI diseases is provided.[11, 3, 1]
Agammaglobulinemia due to absence of B cells
Both the X-linked (Bruton agammaglobulinemia), accounting for 85% of cases, and autosomal recessive forms are associated with extremely low number or absence of B cells. Agammaglobulinemia is characterized by serum IgG levels of less than 100 mg/dl, IgM of less than 20 mg/dl, IgA of less than 10 mg/dl, and peripheral CD-19+ B cell of less than 2%. The principal manifestation is recurrent upper and lower respiratory tract infections. A continual IgRT is an absolute necessity and is life saving. Retrospective analyses of data from agammaglobulinemic children have revealed that the number and severity of infectious complications are inversely correlated with the dose of IVIG administered. Serious bacterial infections and enteroviral meningoencephalitis were prevented when the IgG trough levels were maintained above 800 mg/dl.[31]
Other combined PIs in which the production of antibodies is or can be abnormal
In these disorders, B-cell function and or numbers can be impaired, leading to an inability to generate effective antibody responses. The disorders for which immunoglobulin is variably used fall into three categories: (1) Milder forms of combined immunodeficiencies (such as that caused by partially functional mutations in recombinase-activating genes [RAG]) and (2) Combined immunodeficiencies with associated or syndromic features (such as Wiskott-Aldrich syndrome).
Diseases of immunodysregulation (such as CD27 deficiency). In SCID, immunoglobulin replacement is also necessary in the post-transplantation period, during gene therapy or enzyme replacement (for adenosine deaminase deficiency), until B-cell function is restored.
Hypogammaglobulinemia with impaired specific antibody production
CVID is the prototype of this category. The other includes unspecified hypogammaglobulinemia and hyper-IgM or antibody class-switch deficiency both X-linked type (CD 40L) and autosomal recessive type (activation induced cytidine deaminase, CD40 deficiency). This group is characterized by decreased immunoglobulin concentration and inability to respond with IgG antibody on protein or polysaccharide antigen challenge. These patients are prone for bacterial sinopulmonary infections, chronic lung disease and dysfunction. In patients with CVID early and adequate IgRT has shown to decrease both acute and chronic lung infections and its sequelae.
Normal levels of immunoglobulins with impaired specific-antibody production (selective antibody deficiency)
These patients have normal IgG levels are not hypogammaglobulinemia but have functional disorder with deficient response to polysaccharide antigen with pneumococcal vaccination pose a diagnostic and management challenge. IgRT is considered in settings of recurrent and severe infections, failure of antibiotics treatment or prophylaxis as a first line of treatment, complications of infections or antibiotics, impaired quality of life due to recurrent infections. Many of these patients’ particularly young children may require IgRT for limited time due to spontaneous recovery of responses to polysaccharide vaccine.
Hypogammaglobulinemia with normal-quality antibody response
This group includes transient hypogammaglobulinemia of infancy (THI). In patients with THI the IgG levels are lower than age specific normal during infancy and early childhood with or without lower IgM, IgA levels but specific antibody response is preserved as well as an intact cellular immunity. The definitive diagnosis is made only after correction of the immunoglobulin levels. Antibiotics both for treatment and prophylaxis is the initial step and IgG administration is only considered with antibiotic failure or significant recurrent infections. Continued close monitoring for recovery and excluding other causes of hypogammaglobulinemia is important.
Secondary hypogammaglobulinemia
Secondary hypogammaglobulinemia due to increased IgG loss can occur in may conditions (as discussed earlier) including chylothorax, lymphaniectasia, or protein-losing enteropathy or medications like anti seizure, corticosteroids or rituximab do not warrant IgG administration. However, the FDA has approved use of IgRT in patients with chronic lymphocytic lymphoma (CLL) and recurrent serious bacterial infections, low IgG levels, and sub protective antibody levels after vaccination. Numerous studies have shown the benefit of decreasing documented infections but without survival benefits.[24]
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.
High doses of IVIG may be beneficial in patients with XLA who have enteroviral meningoencephalitis and is also utilized for autoimmune disease associated with primary immune deficiency, such as autoimmune hemolytic anemia.[11, 1]
Identification and treament of infections
Effort should be focused on the treatment of infections, allergic reactions, autoimmune diseases, and gastrointestinal diseases. Aggressive and sometimes 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.[11]
Vaccination
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.[32]
Timely vaccination with pneumococcal conjugate vaccine and sometimes the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is a key component to prevention/treatment of partial B-cell disorders. Guidelines often include recommendations on the order and interval between vaccine administrations to optimize immune response. The Advisory Committee on Immunization Practices (ACIP) recommendations specify the use of either PCV20 alone or PCV15 in series with PPSV23 for all adults aged ≥ 65 years and for adults aged 19–64 years with immune compromise who have not received a PCV or whose vaccination history is unknown.[33]
Although non-live vaccines are deemed unnecessary in persons on replacement Ig because they receive passive antibodies, yearly influenza and COVID vaccines are recommended by many immunologists because the product administered is unlikely to have those vaccines, and if the patient makes any antibody at all, or has any T-cell response, the vaccines to non-live influenza and COVID may be beneficial.
Immune dysregulation
Tumor necrosis factor (TNF) inhibitors and other immune suppression therapies have been used to treat granulomatous diseases and autoimmune disease in patients with CVID.[26]
Hematopoietic stem cell transplant and gene therapy
HSCT is the treatment of choice for patients with SCID.
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.
Gene therapy has been shown some success in reconstituting immune function in infants with X-linked SCID and is also a potential curative therapy for ADA SCID but insertional mutagenesis remains a concern particularly with gammaretroviral vectors. Trials with lentiviral vectors report no mutagenesis to date with follow-up at 4–5 years post treatment.[15, 17, 22]
Secondary hypogammaglobulinemia
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.
Judicious use of antibiotics helps decrease the frequency of infections in patients with hypogammaglobulinemia. Some experts may employ a rotating regimen of antibiotics on a monthly basis to prevent the development of antibiotic resistance and manage recurrent infections.
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. 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.[10, 11, 1]
As reviewed by the American Academy of Allergy, Asthma, and Immunology (AAAAI), the benefit of IgG treatment for these primary immune deficiencies is based on category IIb evidence. IVIG is also approved for B-cell chronic lymphocytic leukemia (B-CLL).[24]
The use of IVIG for primary immune defects with normogammaglobulinemia and impaired specific antibody production is based on category III evidence only.
A safe, effective administration of IgRT requires detailed attention to the selection of patient, patient preferences, product, administration facilities, and health insurance. It is best delivered by an expert in the field who is knowledgeable of diagnosis, treatment, and complexities. The AAAAI and primary immunodeficiency subcommittee has formulated eight guiding principles for successful IgRT therapy.
IVIG
An acceptable starting dose is 400–600mg/kg every 3–4 weeks. After the fifth infusion, a steady state will be achieved. Annual trough levels measurement is enough. Dose or dosing interval needs to be adjusted to achieve optimal goals. Studies support individualizing the IgRT dose, dosing interval, and trough levels rather than a standardized dose in all patients to attain infection-free outcomes. It is best left to the discretion of the treating physician.
SCIG
Usual starting dose is 100–200 mg/kg of body weight each week. The dosing interval is flexible and can be given daily, weekly, biweekly, or monthly. The monthly dosing is only possible with addition of recombinant human hyaluronidase. Infusion rates generally range from 10 to 35 ml/hour/site with an infusion pump with volume of 15–40 ml per site. A 20% SCIG formulation allows lower volume and rate used per manufacturer’s guidelines. Typical sites are lower abdomen, outer thigh, upper arm, and buttock. A steady state can be monitored after 3 months.
Comparison of IVIG and SCIG
View Table
See Table
Some practitioners target trough levels 300 mg/dL higher than pretreatment levels, and trough levels > 800 mg/dL may improve pulmonary outcomes. Some centers advocate a loading dose of 1 g/kg if the patient is agammaglobulinemic.[12, 1]
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 because of convenience 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.[34]
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.
Clinical Context:
Inactive bacterial vaccine that induces active immunization to the serotypes contained in the vaccine. Promotes active immunity against S pneumoniae capsular serotypes 1, 2, 3, 4, 5, 6B 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F
Clinical Context:
Promotes active immunity against S pneumoniae capsular serotypes 1,3,4,5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, which are all conjugated to CRM197 protein.
Clinical Context:
Protection against invasive disease conferred mainly by opsonophagocytic killing of S pneumoniae; contains all serotypes in PCV-13 with the addition of 22F and 33F
Clinical Context:
Protection against pneumococcal disease is conferred mainly by opsonophagocytic killing of S pneumoniae by generated antibodies; PCV-20 contains all the serotypes in PCV-15 with the addition of 8, 10A, 11A, 12F, and 15B
Polyvalent pneumococcal vaccine protects against up to 23 serotypes of S pneumoniae; approximately 70% of invasive diseases caused by S pneumoniae result from these serotypes; protect against the serotypes of S pneumoniae that cause the most severe pneumococcal infections in children.
Clinical Context:
Immune globulins may work via several mechanisms, including the blockage of macrophage receptors, the inhibition of antibody production, the inhibition of complement binding, and the neutralization of pathologic antibodies.
Clinical Context:
Immune globulins neutralize circulating myelin antibodies through anti-idiotypic antibodies; downregulates proinflammatory cytokines, including interferon gamma; block Fc receptors on macrophages; suppress inducer T and B cells while augmenting suppressor T cells; block the complement cascade; promote remyelination; and may increase immunoglobulin G (IgG) in cerebrospinal fluid (10% of cases).
There are many FDA approved IgG preparations available in market with distinct features. The products used in the United States are derived from the plasma of screened donors in the United States The product undergoes several specific treatments to inactivate or remove blood borne pathogens that could be present. The preparations contain highly purified (generally >95 percent) polyvalent IgG. However, there are slight differences in the manufacturing procedures used by different producers, and different stabilizers (eg, sucrose, glucose, maltose or amino acids) used in the excipients making them unique and warrant precaution during substitution of immunoglobulin during treatment. Products also differ in storage requirements and shelf life. It is important for physician to familiarize and select appropriate product for his/her patient. Some of the products are listed below.2
FDA approved Immunoglobulin products available in US 2
How is hypogammaglobulinemia characterized?What are the signs and symptoms of hypogammaglobulinemia?Which physical findings are characteristic of primary hypogammaglobulinemia?What lab tests are performed in the workup of hypogammaglobulinemia?Which imaging studies are performed in the workup of hypogammaglobulinemia?Which lab tests may be considered in the workup of hypogammaglobulinemia?When is biopsy indicated in the workup of hypogammaglobulinemia?When is watchful waiting indicated in the treatment of hypogammaglobulinemia?When is replacement IgG indicated in the treatment of hypogammaglobulinemia?When is IgG replacement indicated in the treatment of secondary hypogammaglobulinemia?What is hypogammaglobulinemia?What is the pathophysiology of hypogammaglobulinemia?What is the prevalence of hypogammaglobulinemia?What is the mortality and morbidity associated with hypogammaglobulinemia?Which patient groups have the highest prevalence of hypogammaglobulinemia?Which clinical history findings are characteristic of hypogammaglobulinemia?Which family history findings are characteristic of hypogammaglobulinemia?What is the typical age of onset for hypogammaglobulinemia?Which microorganisms are associated with hypogammaglobulinemia?What is the role of blood product reactions in the etiology of hypogammaglobulinemia?Which recurrent infection history findings are characteristic of hypogammaglobulinemia?What are the noninfectious GI signs and symptoms of hypogammaglobulinemia?What are the musculoskeletal signs and symptoms of hypogammaglobulinemia?Which autoimmune and collagen vascular diseases are associated with hypogammaglobulinemia?Which growth findings are characteristic of hypogammaglobulinemia?Which lymphoid tissue and organ findings are characteristic of hypogammaglobulinemia?Which developmental abnormalities are characteristic of hypogammaglobulinemia?Which skin and mucous membrane findings are characteristic of hypogammaglobulinemia?Which ENT findings are characteristic of hypogammaglobulinemia?Which pulmonary findings are characteristic of hypogammaglobulinemia?Which cardiovascular findings are characteristic of hypogammaglobulinemia?Which neurologic findings are characteristic of hypogammaglobulinemia?What causes hypogammaglobulinemia?Which genetic B-cell disorders cause hypogammaglobulinemia?What are isolated non-IgG immunoglobulin deficiencies associated with hypogammaglobulinemia?What is IgG subclass deficiency associated with hypogammaglobulinemia?What is specific antibody deficiency (SAD) or specific polysaccharide antibody deficiency (SPAD) associated with hypogammaglobulinemia?What is common variable immunodeficiency (CVID) associated with hypogammaglobulinemia?What causes transient hypogammaglobulinemia of infancy?What is immunodeficiency with thymoma (Good syndrome) associated with hypogammaglobulinemia?What is SCID associated with hypogammaglobulinemia?What is Wiskott-Aldrich syndrome associated with hypogammaglobulinemia?What is ataxia-telangiectasia (A-T) associated with hypogammaglobulinemia?What is nephrotic syndrome associated with hypogammaglobulinemia?What is protein-losing enteropathy associated with hypogammaglobulinemia?Which catabolic disorders cause hypogammaglobulinemia?What is the role of immunosuppressive therapy in the etiology of hypogammaglobulinemia?Which lymphoproliferative malignancies cause hypogammaglobulinemia?What is the role of prematurity in the etiology of hypogammaglobulinemia?What are the drug-related causes of hypogammaglobulinemia?What are the differential diagnoses for Hypogammaglobulinemia?What is the role of serum immunoglobulin measurement in the workup of hypogammaglobulinemia?What is the role of antibody response after immunization in the workup of hypogammaglobulinemia?What is the role of isohemagglutinins testing in the workup of hypogammaglobulinemia?What is the role of peripheral blood lymphocyte immunophenotyping in the workup of hypogammaglobulinemia?What is the role of delayed-type hypersensitivity testing the workup of hypogammaglobulinemia?What is the role of a CBC panel in the workup of hypogammaglobulinemia?What is the role of renal studies in the workup of hypogammaglobulinemia?What is the role of GI studies in the workup of hypogammaglobulinemia?What is the role of chest radiography in the workup of hypogammaglobulinemia?What is the role of HRCT in the workup of hypogammaglobulinemia?How is ADA deficiency diagnosed in hypogammaglobulinemia?How is Wiskott-Aldrich syndrome diagnosed in hypogammaglobulinemia?What is the role of prenatal testing in the workup of hypogammaglobulinemia?Which histologic findings are characteristic of the workup of hypogammaglobulinemia?How is hypogammaglobulinemia treated?How is agammaglobulinemia due to absence of B cells treated?How is hypogammaglobulinemia in primary immunodeficiencies treated?How is hypogammaglobulinemia with impaired specific antibody production treated?How is hypogammaglobulinemia with selective antibody deficiency treated?How is hypogammaglobulinemia with normal-quality antibody response treated?How is secondary hypogammaglobulinemia treated?What is the role of IgG replacement therapy in the treatment of primary hypogammaglobulinemia syndromes?What is the focus of treatment for secondary hypogammaglobulinemia?What is the role of live vaccines in the treatment of hypogammaglobulinemia?What is the role of high dose IVIG in the treatment of hypogammaglobulinemia?How is ADA deficiency treated in hypogammaglobulinemia?What is the role of TNF in the treatment of hypogammaglobulinemia?What is the role of gene therapy in the treatment of hypogammaglobulinemia?What is the role of PCV13 and PPSV23 vaccines in the treatment of hypogammaglobulinemia?Which activity modifications are used in the treatment of hypogammaglobulinemia?What is the role of medications in the treatment of hypogammaglobulinemia?Which medications in the drug class Blood Product Derivatives are used in the treatment of Hypogammaglobulinemia?Which medications in the drug class Vaccines are used in the treatment of Hypogammaglobulinemia?
Elizabeth A Secord, MD, Professor (Clinical), Division Chief of Allergy and Immunology, Medical Director of Horizons Project for Pediatric and Adolescent HIV Treatment and Prevention, Director, Primary Immune Deficiency Clinic, Department of Pediatrics, Wayne State University School of Medicine; Physician, Division of Allergy, Immunology and Rheumatology, Children's Hospital of Michigan (Detroit Medical Center)
Disclosure: Received research grant from: Novavax; pfizer; gilead.
Coauthor(s)
Divya Seth, MD, Assistant Professor in Pediatric Allergy and Immunology, Department of Pediatrics, Wayne State University School of Medicine; Clinical Educator, Children’s Hospital of Michigan
Disclosure: Nothing to disclose.
Milind Pansare, MBBS, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy/Immunology, Children's Hospital of Michigan, Wayne State University School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
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
Disclosure: Have a 5% or greater equity interest in: Secretory IgA, Inc. ; siRNAx, Inc.<br/>Received income in an amount equal to or greater than $250 from: siRNAx, Inc.
Chief Editor
Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy
Disclosure: Nothing to disclose.
Additional Contributors
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: 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.
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.
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.
References
Orange JS, Ballow M, Berger M. Position statement on the appropriate use of intravenously administered immunoglobulin (IGIV). 2011.
Ochs HD, Smith CIE, Puck JM. Primary Immunodeficiency Diseases: A molecular and genetic approach. 2nd ed. Oxford University Press; 2007.
Camiolo M, Gauthier M, Cohn L, Ray A. Biology of Lymphocytes. Burks WA, Holgate ST, O’Hehir RE, et al. Middleton's Allergy 2-Volume Set: Principles and Practice. 9th ed. Elsevier; 2020. 924-1007.
Buckley RH, Orange JS. Primary Immunodeficiency Diseases. Burks WA, Holgate ST, O’Hehir RE, et al. Middleton's Allergy 2-Volume Set: Principles and Practice. 9th ed. Elsevier; 2020. 5196-5334.
Institute of Medicine (US) Vaccine Safety Committee. Stratton KR, Howe CJ, Johnston RB Jr. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: National Academies Press; 1994.
Summary of Risk-based Pneumococcal Vaccination Recommendations. Centers for Disease Control and Prevention. Available at https://www.cdc.gov/pneumococcal/hcp/vaccine-recommendations/risk-indications.html. June 27, 2024; Accessed: Aug 26, 2024.
