AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

B lymphocytes, named after their site of origin in the bursa of Fabricius in birds or in the bone marrow in humans, form the basis for humoral immunity by their production of immunoglobulins. B-cell disorders are divided into defects of B-cell development/immunoglobulin production (immunodeficiencies) or excessive/uncontrolled proliferation (lymphomas, leukemias).

This article reviews B-cell immunodeficiencies, with emphasis on pathophysiology, clinical presentation, laboratory evaluation, treatment, and prognosis.

Pathophysiology

During fetal development, hematopoiesis, including lymphopoiesis, is multicentric. After birth, the bone marrow becomes the exclusive production site for lymphoid progenitors. B and T cells, type 2 dendritic cells, and natural killer (NK) cells share a common ancestor, ie, common lymphoid progenitor (CLP). CLP differentiates into 2 intermediate progenitors: early B cells and T/NK/dendritic trilineage cells. Both continue their development in the bone marrow through an antigen-independent process called primary lymphopoiesis (PL). Recognized stages of PL are pro-B cell, pre-B cell, immature B cell, and mature B cell.

Secondary B lymphopoiesis is an antigen-dependent process and occurs in the germinal center of peripheral lymphoid organs with specific antibody production. Secondary T lymphopoiesis is also an antigen-dependent process and occurs in the thymus.

Secondary lymphopoiesis (SL) begins when mature B cells enter the extrafollicular area of lymphoid tissue and differentiate into short-lived plasma cells and memory cells after first being stimulated by antigen-presenting cells. Memory cells travel to the primary follicle, where, after exposure to dendritic cells, they differentiate into centroblasts (immunoglobulin class-switch). Centroblasts progress to centrocytes with high-affinity antibody production, and then they differentiate further to long-term memory cells and plasmablasts. The latter migrate back to the bone marrow and start producing immunoglobulins.

The earlier the defect, the more devastating the effect on lymphopoiesis. Defects occurring at the CLP stage or those affecting processes common to B- and T-cell development result in combined immunodeficiency involving B, T, and NK cells (see Combined B-Cell and T-Cell Disorders).

The human immune system is capable of producing up to 10⁹ different antibody species to interact with a wide range of antigens. Named after the heavy-chain isotype, 9 isotypes are known: immunoglobulin G (IgG) 1, IgG2, IgG3, IgG4, immunoglobulin M (IgM), immunoglobulin A (IgA) 1, IgA2, immunoglobulin D (IgD), and immunoglobulin E (IgE). Immunoglobulin gene rearrangement begins with heavy-chain gene rearrangement followed by light-chain gene rearrangement.

Following B-cell receptor activation, 2 waves of tyrosine kinase phosphorylation occur. The first wave involves the Src family of tyrosine kinases, ie, Lyn, Blk, Fyn, and Lck; the second activates Bruton tyrosine kinase and Syk.

X-linked agammaglobulinemia (XLA), also known as Bruton agammaglobulinemia, is the result of a mutation of the BTK gene. Pro-B cells are present in normal number, but they are unable to mature to pre-B cells. The BTK gene is present on Xq21.3-q22, and its defect results in deficiency of Bruton tyrosine kinase. Non-XLA is the result of mu heavy-chain gene deficiency that leads to abortive production of IgM and failure of B-cell development.

Activated tyrosine kinases generate a second wave of messengers by activating serine/threonine kinases or phosphatases pathways. Three major pathways have been identified: the inositol phospholipid hydrolysis pathway, the phosphatidyl inositol-3-kinase pathway, and the Ras pathway. These pathways converge toward the activation of transcription factors, resulting in B-cell activation and proliferation.

SL is an antigen-dependent process and requires the collaboration of antigen presenting cells (dendritic cells and macrophages), CD4⁺ T lymphocytes, and different cytokines. The B-cell receptor is formed from the noncovalent association between surface IgM or IgD and 2 transmembrane proteins, IgA and immunoglobulin B. The presence of CD22 and CD19/CD21 on the cell surface, playing the role of coreceptorlike molecules, is necessary for the activation of the receptor. However, a complete functional response requires the intervention of the costimulatory molecule CD40 and the action of soluble cytokines. Immunoglobulin class-switching requires the interaction of CD40 with CD40 ligand (or gp39) present on the surface of B and T lymphocytes, respectively.

X-linked immunodeficiency with hyper-IgM (XHM) is related to a deficiency in gp39 (CD40 ligand). B cells can initiate the immune response by producing IgM, but they are not capable of operating the class-switching, hence the overproduction of IgM and the decrease or absence of the other immunoglobulin isotypes. Liver disease, sclerosing cholangitis, and liver/GI malignancies are common in these patients. The expression of CD40L on the surface of biliary epithelial cells has suggested a role for CD40-CD40L interaction in the pathogenesis of these complications through defective control of intracellular pathogens such as Cryptosporidium parvum, recently recognized as an important pathogen in these patients.

In common variable immunodeficiency (CVID), mature B cells are normal in number and morphology but fail to differentiate to plasma cells because of defective interaction between T and B cells, mostly caused by a T-cell defect. This defect is thought to be related to a decreased number and/or function of CD4⁺ T lymphocytes or, occasionally, to an increased number of CD8⁺ T lymphocytes. However, abnormal responses of B cells to many usual stimuli have also been identified in vitro.

The underlying abnormality in selective IgM deficiency is a defect of helper T-cell and excessive suppressor T-cell activity. The disorder is characterized by a low level of IgM. IgG levels are normal, but the IgG response is usually decreased.

Helper T-lymphocyte deficiency has been incriminated in the pathogenesis of transient hypogammaglobulinemia of infancy (THI) and immunodeficiency with thymoma.

The primary defect in selective IgA deficiency is related to a failure of B cells to differentiate to mature isotype-switched surface IgA-positive B cells and IgA-secreting plasma cells with appropriate stimuli. The basis for the defect is not known. B cells from patients with IgA deficiency activated via CD40 and interleukin-10 are capable of synthesizing and secreting IgA. Defective helper T-cell and excessive suppressor T-cell activities are occasionally present. Cytokine abnormalities have also been described.

IgG2 is the most common of IgG subclass deficiencies. It occurs either alone or with IgG4 or IgA deficiency. Its hallmark is an inability to generate antibodies to polysaccharides.

Primary B-cell disorders result in a complete or partial absence of one or more immunoglobulin isotypes. Regardless of the primary cause, the symptoms depend on the type and severity of the immunoglobulin deficiency and the association of cell-mediated immunodeficiency. In general, severe immunoglobulin deficiency results in recurrent infections with specific microorganisms in certain anatomical sites.

Immunoglobulins play a dual role in the immune response by recognizing foreign antigens and triggering a biological response that culminates in the elimination of the antigen. Their role in the fight against bacterial infections has been recognized for many years. Emerging evidence from animal and clinical studies suggests a more important role for humoral immunity in the response to viral infections than what was initially thought.

IgM plays a pivotal role in the primary immune response. IgG is the major component, comprising approximately 85% of serum antibodies. They mediate many functions, including antibody-dependent cell-mediated cytotoxicity, phagocytosis, and clearance of immune complexes, by binding to the Fc receptors. IgG1 is the major component of the response to protein antigens (eg, antitetanus/diphtheria antibodies). IgG2 is produced in response to polysaccharide antigens (eg, antipneumococcal antibodies), and IgG3 seems to play an important role in the response to respiratory viruses. Complement fixation and activation are carried out by IgG1, IgG3, IgM, and, to a lesser degree, IgG2. IgA and, to a lesser extent, IgM, produced locally and secreted in the secretions of mucous membranes, are the major determinants of mucosal immunity.

IgG antibodies are the only immunoglobulin class that crosses the placenta and provides the infant with effective humoral immunity during the first 7-9 months of life.

Frequency

United States

Acquired B-cell disorders are far more common than genetic disorders affecting B cells. Antibody deficiency disorders comprise 50% of all primary immunodeficiencies. The first and second most common B-cell disorders are IgA deficiency and CVID, with incidence estimated at 1 case in 700 persons and 1 case in 53,000-100,000 persons of European ancestry, respectively. Selective IgM deficiency is a rare disorder. Although IgG4 deficiency is very common (detected in 10-15% of the general population), its impact on carriers is not well defined. Wiskott-Aldrich syndrome (WAS) is a rare disease. Estimates indicate that 500 Americans have the disease, with an annual incidence of 40-50 cases per year.

International

Worldwide, malnutrition comprises the majority of all antibody deficiency syndromes.

Mortality/Morbidity

Patients with B-cell disorders have decreased immunoglobulin levels (hypogammaglobulinemia), with its consequence of an increased incidence of early recurrent infections, which may ultimately lead to significant damage involving different organs, particularly the respiratory system.

• Autoimmune disorders and cancer, also more common in this group of patients, result in significant morbidity and mortality.
• Mortality rates in infants and young children are increased, and survivors may sustain different degrees of growth retardation. For example, without allogeneic bone marrow transplantation, most patients with X-linked severe combined immunodeficiency (XSCID) die before their second year of life and those with WAS die by age 11 years. Most patients with reticular dysgenesis die in early infancy. Despite immunoglobulin therapy, 15% of patients with XLA die of infectious complications by age 20 years.
• Therapies for these disorders (eg, intravenous immunoglobulin [IVIG], bone marrow transplantation, gene therapy) are very costly and require highly advanced facilities.

Race

No racial or ethnic predilection is recognized.

Sex

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

• X-linked disorders such as XLA, XHM, XSCID, and WAS affect only males. Females are carriers and thus transmit the disease to male offspring.
• CVID and IgA deficiency have no sex predilection, but familial clustering and a frequent association with autoimmune disorders have been described.

Age

The age of patients at onset of clinical symptoms depends on several factors, including the degree of the immunoglobulin deficiency and whether the failure of the immune system is abrupt or progressive. Certain genetic disorders may not become clinically evident until late childhood or adulthood. However, most of these disorders are symptomatic by the second half of the first year of life.

• Symptoms in XLA begin at age 7-9 months, after a significant decline of maternal antibodies occurs and in contrast to T-cell disorders and severe combined immunodeficiencies (SCIDs), in which recurrent infections start at a younger age. In XHM, symptoms begin during the first 2 years of life.
• IgA deficiency is usually asymptomatic in childhood, and many patients are diagnosed in early adulthood.
• Immunodeficiency with thymoma (Good syndrome) affects adults aged 40-70 years. CVID is characterized by a varying age at onset but usually manifests by the third decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

A history of recurrent infections is a common presenting feature. The onset of symptoms in childhood is suggestive of an inherited disorder. Patients with B-cell deficiencies begin having bacterial infections when aged 7-9 months, when the placental antibodies fall to undetectable levels. Patients with primary T-cell deficiency or SCID begin having infections 3-4 months after birth. Acquired B-cell disorders may start in persons of any age, depending on the underlying cause.

The site of infection may provide clues to the significance and the type of immune deficiency. Upper and lower respiratory infections, skin infections, meningitis, bacteremias, and abscesses are common in persons with B-cell disorders. Pneumonia with Pneumocystis carinii or cytomegalovirus (CMV), disseminated bacille Calmette-Guérin infection or atypical mycobacterial infection, and recurrent or persistent skin candidiasis are suggestive of T-cell disorders of SCID. Diarrhea with failure to thrive in children with SCID is usually related to viral infections (eg, rotaviruses, adenoviruses).

The type of microorganisms involved is also suggestive. Antibody deficiency is associated with recurrent infections with encapsulated bacteria. Giardia lamblia infection is very common in patients with CVID or IgA deficiency. Opportunistic infections with fungi, viruses, or intracellular bacteria are particularly common in patients with T-cell disorders or SCID.

An adverse reaction to transfused blood products or to vaccines should raise the possibility of an underlying immunodeficiency, particularly IgA deficiency.

A thorough family history is crucial in the evaluation of inherited disorders. Both XLA and hypogammaglobulinemia with hyper-IgM are X-linked disorders. CVID and IgA deficiency may be familial and are frequently associated with autoimmune disorders.

• X-linked agammaglobulinemia
• • The disorder affects boys only and is characterized by recurrent pyogenic infections during the second half of the first year of life.
  • Sinopulmonary infections are the most common (60% of patients), with chronic otitis media, sinusitis, and pneumonia. The other common infections, in decreasing order, are gastroenteritis (35%), pyoderma (25%), arthritis (20%), and meningitis/encephalitis (16%). Septicemia (10%), conjunctivitis (8%), and osteomyelitis (3%) are less common.
  • Diarrhea with monoarthritis or oligoarthritis of large joints with sterile effusion is occasionally observed.
  • Patients with XLA have an increased frequency of leukemia and lymphoma.
  • The encapsulated bacteria Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Staphylococcus aureus are the most common pathogens.
  • The frequency of viral and fungal infections and tuberculosis is not increased because cellular immunity is normal. However, live viral vaccines (eg, poliovirus vaccine) are not well tolerated and may result in viremia because of the lack of IgA. G lamblia and Rotavirus are frequently associated with the GI symptoms. Ureaplasma urealyticum is implicated in the pathogenesis of sterile arthritis; however, in many cases, the arthritis is related to direct bacterial infection.
• X-linked immunodeficiency with hyper-IgM
  • XHM affects only boys. The IgM level is elevated; the levels of all the other immunoglobulins are decreased. Recurrent infections of the upper and lower respiratory tracts beginning during the first 2 years of life are common. The susceptibility to P carinii and C parvum, both opportunistic infections controlled by cellular immunity, may be explained by the nature of the defect underlying this disease and involving T-cell CD40L.
  • These patients have a high incidence of liver disease, sclerosing cholangitis (approximately 20% of patients in a series reported by Levy et al; 80% by age 20 y reported by others), and liver/GI malignancies.
  • Oral and rectal ulcers are common in patients with chronic neutropenia.
  • Autoimmune diseases such as arthritis, nephritis, and hematologic disorders have also been reported.
• Selective IgA deficiency
• • IgA deficiency may be primary or secondary (acquired), sporadic, or familial. Both serum and secretory IgA are lacking in most patients and, rarely, one or the other. Inheritance is either autosomal recessive or dominant. Administration of certain drugs, such as phenytoin, D-penicillamine, sulfasalazine, and hydroxychloroquine, has been incriminated in this entity. Cases of congenital noninherited IgA deficiency in association with rubella, CMV, and Toxoplasma gondii have been reported.
  • Although certain studies have reported recurrent infections in as many as 50% of IgA-deficient patients, most of these individuals are healthy. Some patients develop symptoms after an uneventful childhood and early adulthood. Recurrent or chronic upper and lower respiratory tract infections may result in bronchiectasis or cor pulmonale in insufficiently treated patients. G lamblia infection of the GI tract is common. Other GI diseases, such as spruelike syndrome, ulcerative colitis, and Crohn disease, have been reported.
  • The incidence of autoimmune and collagen vascular diseases is increased (up to 25% of patients in certain studies). Rheumatoid arthritis, systemic lupus erythematosus without renal disease, autoimmune hepatitis, hemolytic anemia, and endocrinopathies have been described.
  • Patients with undetectable levels of IgA antibodies may develop anti-IgA antibodies after receiving blood products. Once sensitized, these patients are at risk of anaphylactic reactions if they receive blood products containing even small amounts of IgA antibodies. Mounting an antibody response to cow milk protein is also common.
  • Several factors explain the variability of clinical expression of this disorder. Symptoms may be attenuated by the increased excretion of monomeric IgM in the secretions of these patients, compensating for the lack of IgA, or they may be worsened by the association of an IgG subclass deficiency such as IgG2/IgG4 or IgG3.
• Selective IgM deficiency:
• • This is a rare disorder associated with recurrent and life-threatening infections with encapsulated bacteria, particularly pneumococcal and meningococcal species.
  • IgG levels are usually normal, but the response to specific infections is reduced.
• IgG subclass deficiency
• • This is defined as a decrease of an IgG subclass greater than 2 standard deviations below the normal mean for age. One or more IgG subclasses may be involved. This deficiency may be isolated or associated with other immunodeficiencies. Unless a patient has an impaired response to tetanus, diphtheria, and pneumococcal vaccine, IgG deficiency is not considered clinically significant. IVIG should not be used in these patients until a thorough antibiotic trial has failed to control their infections.
  • IgG1 deficiency is rare. The more common IgG2 deficiency is associated with an inability to mount an antibody response to polysaccharides and to recurrent sinopulmonary infections with encapsulated bacteria such as H influenzae and S pneumoniae. Asymptomatic cases of IgG2 deficiency have been reported.
  • IgG3 is necessary to generate an antibody response to viral infections and Moraxella catarrhalis. Its deficiency is associated with recurrent sinopulmonary infections with these pathogens. IgG4 subclass deficiency is very common, affecting 10-15% of the general population. It may be isolated or associated with other IgG subclass deficiencies. The clinical significance of this disorder remains controversial.
• Transient hypogammaglobulinemia of infancy
• • THI is related to a delayed onset of immunoglobulin synthesis in infants. These patients recover a normal antibody response when aged 2-3 years.
  • During their first years, these patients have a high incidence of recurrent upper respiratory infections but not of pneumonias or life-threatening infections. These patients do not require IVIG therapy.
• Common variable immunodeficiency
• • CVID is the most common cause of hypogammaglobulinemia and affects both sexes equally. It encompasses a group of disorders that are heterogeneous in their mechanism and age of onset. Although a first manifestation in infancy and childhood is possible, symptoms typically become evident between the second and third decades of life.
  • Recurrent upper and lower respiratory infections, such as otitis media, sinusitis, pneumonia, and bronchitis, are the most common symptoms. Arthralgia and conjunctivitis are frequently reported. Pyoderma, urinary tract infection, osteomyelitis/arthritis, and meningitis/encephalitis are less common. Gastritis with achlorhydria and pernicious anemia may be observed. Diarrhea occurs in 60% of patients with CVID.
  • Encapsulated bacteria such as S pneumoniae, S pyogenes, and H influenzae are the most common pathogens. Bordetella pertussis plays an important role in respiratory infections. G lamblia and Campylobacter species are involved in GI manifestations.
  • Infections with fungi, mycobacteria, and P carinii are not usually encountered unless an associated deficiency of cellular immunity exists. Severe abnormalities of cell-mediated immunity are occasionally reported. In these patients, severe and prolonged primary varicella or zoster, herpes simplex, and CMV infections have been reported.
• Kappa/lambda light-chain deficiency: These are rare disorders that manifest clinically as upper respiratory tract infections, malabsorption syndrome with diarrhea, and pernicious anemia.
• Immunodeficiency with thymoma
• • Also known as Good syndrome, this disorder is typically described in adults aged 40-70 years. Thymoma of the benign spindle cell variety may be an incidental finding on images from a routine chest radiograph, but it is more often discovered during an evaluation for hypogammaglobulinemia. Of patients with thymoma, 3-6% have concomitant hypogammaglobulinemia or are found to have it upon follow-up examinations.
  • The decrease of immunoglobulins affects all isotypes and results in recurrent sinopulmonary infections and diarrhea, which may be ascribed to an infectious cause in only a third of cases. Pure red cell aplasia, agranulocytosis, and myasthenia gravis may be associated with this disorder and may improve after thymectomy, although the hypogammaglobulinemia does not. Half the patients have cell-mediated immunodeficiency and may present with mucocutaneous candidiasis, CMV, herpes zoster infection, or P carinii pneumonia.
• IgE hypogammaglobulinemia
• • Compared to controls, patients with decreased IgE levels have a higher incidence of autoimmune diseases (47% vs 15%), nonallergic reactive airway disease (73% vs 20%), and arthralgia and chronic fatigue.
  • The most common autoimmune diseases described with this entity are thyroid disease, rheumatoid arthritis, Sjögren syndrome, Raynaud syndrome, and systemic lupus erythematosus.
• Omenn syndrome
• • This syndrome is characterized by high serum IgE levels, decreased levels of the other immunoglobulins, and hypereosinophilia. It manifests in early infancy as chronic diarrhea, failure to thrive, and an erythematous rash with desquamation. Hepatosplenomegaly is common.
  • Patients die in the first few months of life unless a successful allogeneic bone marrow transplantation is performed.
• Hyperimmunoglobulin E syndrome
  • Also known as Job syndrome, hyperimmunoglobulin E (HIE) syndrome is also characterized by very high levels of serum IgE. However, the normal IgA, IgG, and IgM levels and the clinical presentation differentiate it from the previous disorder.
  • Beginning in early infancy, patients present with recurrent staphylococcal infections of the skin, joints, lungs, and other viscera. Grimbacher et al reported the results of their study of 30 patients with HIE syndrome. In addition to the previous symptoms, 72% of patients had delayed shedding of primary teeth, 57% had recurrent fractures, 76% had scoliosis and characteristic facial features, and 68% had hyperextensible joints. Atopiclike dermatitis may occur.
  • The inheritance in this disorder is autosomal dominant with variable expression.

Physical

• Growth and development: Early-onset recurrent infections cause growth retardation. However, normal growth does not exclude the presence of these disorders. Developmental abnormalities such as short-limbed dwarfism and hair abnormality are observed in cartilage-hair syndrome.
• Lymphoid tissue and organs: A paucity of tonsils, adenoids, and peripheral lymph nodes is observed in persons with XLA and in those with different forms of SCID. Diffuse lymphadenopathy is observed in persons with CVID, immunodeficiency with hyper-IgM, and Omenn syndrome; splenomegaly occurs in 25% of CVID patients with or without hypersplenism.
• Skin and mucous membranes: Permanent scars are observed following skin infections. An eczematous rash develops in persons with HIE syndrome, and a desquamating erythematous rash develops in those with Omenn syndrome. Livedo reticularis with muscle weakness or dermatomyositislike syndrome may be observed with XLA. A lupuslike rash may occur.
• Ear, nose, and throat: Evidence of past perforations, scarring, and dull tympanic membranes occur after recurrent episodes of otitis media. Purulent nasal discharge, a cobblestone pattern of pharyngeal mucosa, and postnasal exudate may be evident. The presence or absence of tonsillar tissue should be noted.
• Cardiovascular system: Signs such as a loud pulmonic heart sound, right ventricular heave, and tricuspid regurgitation murmur should be sought; if present, they support the diagnosis of pulmonary hypertension. Jugular venous distension, tender hepatomegaly, and lower-extremity edema suggest cor pulmonale.
• Pulmonary system: Rales, rhonchi, wheezing, and digital clubbing may be encountered.
• Neurologic system: Following vaccination, paralytic poliomyelitis may ensue in patients with antibody deficiency. Deep sensory loss with decreased vibratory sense and position of limb segments are observed in persons with pernicious anemia.

Causes

• Pure B-cell disorders
• • X-linked agammaglobulinemia
  • X-linked immunodeficiency with hyper-IgM
  • Selective IgA deficiency
  • Selective IgM deficiency
  • IgG subclass deficiency
  • Transient hypogammaglobulinemia of infancy
  • Common variable immunodeficiency
  • Kappa/lambda light-chain deficiency
  • Immunodeficiency with thymoma
  • IgE hypogammaglobulinemia
  • HIE syndrome
• Combined T- and B-cell deficiencies: These disorders combine symptoms related to both B- and T-cell deficiency (see Combined B-Cell and T-Cell Disorders).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The evaluation of patients with possible B-cell disorders should include a quantitative measurement of serum immunoglobulins and IgG subclasses. If the findings from these studies are within reference ranges and the likelihood remains that the patient has a humoral immunodeficiency, the antibody response to specific antigens (polysaccharide or protein antigens) should be evaluated further. In SCID patients presenting with recurrent infections in the first months of life, immunoglobulin levels are not helpful in the diagnosis because of the persistence of maternal antibodies.
• Levels of serum immunoglobulin
• • Serum protein electrophoresis is appropriate for presumptive diagnosis of hypogammaglobulinemia or monoclonal protein. Quantitative methods are used for the precise measurements of each immunoglobulin isotype. Enzyme-linked immunosorbent assay is used for IgE quantitation.
  • Values should be compared with age-standardized reference ranges for each laboratory. The following ranges are examples of values used for the adult population:
    • IgG1 - 500-1200 mg/dL
    • IgG2 - 200-600 mg/dL
    • IgG3 - 50-100 mg/dL
    • IgG4 - 20-100 mg/dL
    • IgM - 50-150 mg/dL
    • IgA1 - 50-200 mg/dL
    • IgA2 - 0-20 mg/dL
    • IgD - 0-40 mg/dL
    • IgE - 0-0.2 mg/dL
  • In most disorders involving IgG, its level is less than 200-250 mg/dL with variable levels of the other immunoglobulins, depending on the underlying disease.
• Immunoglobulin subclasses: Immunoglobulin subclass deficiency is defined as a decrease of an IgG subclass by more than 2 standard deviations below the normal mean for age.
• Antibody response after immunization
• • This response may be absent. Antitetanus/diphtheria antibodies (IgG1), antipneumococcal polysaccharide antibodies (IgG2), and antirespiratory virus antibodies (IgG3) should be checked if the titers for total immunoglobulins are normal and the patient is unable to produce antibodies to specific antigens.
  • This response may be evaluated by measuring antitetanus and antipneumococcal titers 3-4 weeks after vaccination; a 4- and 2-fold rise, respectively, is considered normal.
• Isohemagglutinins
• • IgM antibodies to A and B blood group antigens (isohemagglutinins) should be checked if the other test results are normal and the patient is unable to mount a response to specific antigens.
  • The absence of isohemagglutinins is a significant finding suggestive of an immunoglobulin production problem.
• Evaluation of cellular immunity (see Combined B-Cell and T-Cell Disorders)
• • Measure peripheral blood lymphocyte levels.
  • Perform lymphocyte phenotyping using flow cytometry.
  • Evaluate T-lymphocyte number and function.
  • Determine the helper-to-suppressor (CD4-to-CD8) T-cell ratio.
  • Assess delayed-type skin hypersensitivity.
• Autoantibodies and antibodies to IgA
• • These occur in more than 20% of patients with IgA deficiency. They are not predictive of adverse reactions to blood products containing IgA.
  • Autoantibodies and antibodies to food antigens (eg, cow milk) may be present in patients with IgA deficiency.
• Results in specific B-cell disorders
• • For XLA, serum immunoglobulin levels are low, with an IgG level of less than 100 mg/dL. Response to immunization is absent. Isohemagglutinins are absent. B-lymphocyte numbers in the peripheral blood are decreased or absent, while T-lymphocyte numbers are normal. Genetic analysis helps make the final diagnosis.
  • For CVID, serum immunoglobulin levels, especially those of IgA and IgG, are low. The immunization response is decreased. The B-lymphocyte count in the peripheral blood is normal in more than 75% of patients. The T-lymphocyte count is normal in most patients, but it may be decreased with a reversal of the CD4-to-CD8 T-cell ratio.
  • For selective IgA deficiency, the serum IgA level is less than 5 mg/dL, with normal IgG and IgM levels. Both IgA1 and IgA2 levels are usually decreased. The IgE level is decreased in 25% of these patients. IgG2 and IgG4 levels may be decreased, especially in patients with sinopulmonary infections. Because IgA deficiency may be a transient phenomenon, IgA and IgG measurements should be repeated after a period of observation. Anti-IgA antibodies are present in more than 20% of patients. Their presence does not correlate with the occurrence of an anaphylactic reaction to IgA-containing blood products. Autoantibodies to the adrenal gland, parietal cells, pancreatic islets, smooth muscle, thyroglobulin, immunoglobulins, and nuclear proteins are observed. Antibodies to food antigens (eg, cow milk) can be observed.
  • For XHM, IgM is markedly increased to levels frequently higher than 1000 mg/dL. Normal levels do not exclude the diagnosis because these have been found in 29 of 55 patients with genetically proven XHM. IgG, IgA, and IgE levels are decreased, as are the numbers of lymphocytes bearing these antibodies. IgM response to antigen exposure is possible, but the IgG and IgA responses are absent or diminished. Cell-mediated immunity is defective in some patients despite normal T-lymphocyte counts. Chronic neutropenia may be present in some patients.
  • For IgG subclass deficiency, one or more IgG subclasses and other immunoglobulin isotypes may be involved. Levels of one or more IgG subclasses may be decreased. Quantitation of the immunoglobulin response to polysaccharide and protein antigens (eg, pneumococcal vaccine, tetanus toxoid) provides more information than simple measurements of IgG subclasses. Total immunoglobulin levels are normal or increased. Antibodies to specific antigens (proteins or polysaccharides) may be defective.
  • For immunodeficiency with thymoma, a decreased IgG level is the most common finding, followed by decreased IgM and IgA levels. Absolute lymphopenia is also common. B-lymphocyte levels in the peripheral blood are frequently decreased. Absolute CD4⁺ T lymphocyte numbers may be decreased, with reversal of the CD4-to-CD8⁺ T-cell ratio. Absent skin hypersensitivity reactions are documented in many cases, with abnormal in vitro lymphocyte proliferation assay findings in some patients. All patients with thymoma should have their immunoglobulin levels quantitated at baseline and then periodically.
  • For IgE hypogammaglobulinemia, the radioallergosorbent test measures serum IgE levels to 60 regional seasonal and nonseasonal allergens and returns a negative finding in persons with this disease. Skin test results to the same allergens are also negative. A decreased IgE level (<2.5 IU/mL) is the only finding in 43% of these patients. Of all cases, 57% are associated with depressed serum levels of other immunoglobulins.
  • For isolated immunoglobulin deficiency (ie, IgM, IgA), IgM or IgA levels are low, whereas the rest of the immunoglobulin levels are normal.
  • For THI, B and T lymphocytes are normal in number and T-cell function is normal. Isohemagglutinin production is normal. Infants produce antitetanus and diphtheria antibodies by age 6-11 months. Immunoglobulin levels normalize by age 2-3 years.
  • For HIE syndrome, most patients have increased IgE, to levels higher than 480 mcg/dL (reference range, <24 mcg/dL). Eosinophilia is common. IgM, IgG, and IgA levels are usually within the reference range. Levels of anti–S aureus IgE and IgM antibodies are markedly higher than matched controls, and levels of anti–S aureus IgG and especially IgA are significantly lower than in controls.
  • For Omenn syndrome, serum IgE levels are increased. The levels of other immunoglobulins are decreased. Hypereosinophilia is observed.

Imaging Studies

• Chest radiographs
• • Most patients with CVID and primary hypogammaglobulinemia develop pulmonary complications that might be visible on chest radiographs.
  • Interstitial infiltrate, bronchiectasis, emphysema or bullae, and scarring may be evident; however, radiographic findings may be normal, and only high-resolution CT (HRCT) scans can reveal the abnormalities.
• High-resolution CT scans
• • HRCT scans may be the criterion standard to study lung abnormalities in these patients.
  • Patients with CVID and primary hypogammaglobulinemia may develop pulmonary fibrosis, bronchiectasis, parenchymal scarring, pleural thickening, and, less commonly, emphysema or parenchymal nodules.
  • Follow-up monitoring with HRCT scans sometimes reveals silent and asymptomatic deterioration despite appropriate IVIG therapy.
  • The role and therapeutic implications of clinical findings with this test have recently been discussed. Some authors recommend intensification of immunoglobulin therapy to achieve higher trough levels.

Other Tests

• Lymph node biopsy: This test reveals the absence of plasma cells, lymphoid follicles, or germinal centers in persons with XLA. In those with XHM, follicles and germinal centers are absent but plasma cells may be identified.
• Intrauterine diagnosis: This can be performed by restriction fragment length polymorphism for X-linked defects.
• Polymerase chain reaction: This may be helpful in the diagnosis of enteroviral meningoencephalitis or JC virus (polyomavirus) infection.
• Brain biopsy may be needed to confirm the diagnosis of these disorders.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• IVIG replacement therapy is the treatment of choice for most primary B-cell disorders with hypogammaglobulinemia, including XLA, CVID, immunodeficiency with thymoma, and most of the combined immunodeficiencies. Do not administer IVIG to patients with IgG subclass deficiency unless they do not produce antibodies and do not respond to prophylactic antibiotics.
• • Quartier et al reported on 31 XLA patients treated early in life with IVIG. The higher the trough level of immunoglobulin, the lower the incidence of acute bacterial infections requiring hospitalization, with the best results obtained with levels of more than 800 mg/dL and the worst results with levels of less than 500 mg/dL. However, chronic bronchitis and sinusitis were not prevented by this treatment.
  • IVIG is not indicated in persons with selective THI.
  • IVIG is not indicated for IgG subclass deficiency unless a broader deficiency of antibody production is present.
  • For selective IgA deficiency, IVIG therapy is not indicated. Oral administration of immunoglobulin may improve chronic diarrhea. Immunoglobulin preparations containing low levels of IgA and washed blood products should be used in cases of concomitant IgG deficiency.
  • High doses of IVIG or intrathecal immunoglobulin may be beneficial in enteroviral meningoencephalitis.
• Do not immunize these patients with live attenuated vaccines.
• Focus efforts on the treatment of infections, allergic reactions, and autoimmune and GI diseases. Aggressive and prolonged antibiotic therapy covering S pneumoniae and H influenzae is indicated. Prophylactic antibiotic therapy has been recommended for patients with frequent infections. A course of metronidazole may result in dramatic improvement of the diarrhea and, to a certain extent, of malabsorption syndrome. Prophylactic antibiotic therapy may significantly decrease the incidence of infections.
• Interleukin-2 may improve in vitro lymphocyte function in persons with CVID. However, because of limited use in humans, no final conclusions can be made regarding its efficacy.
• Parenteral vitamin B-12 is used in persons with pernicious anemia.

Activity

Encourage physical activity.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Immunoglobulins

Provide immediate passive immunity. Replacement therapy in antibody deficiency states.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Regular follow-up monitoring of the following parameters is necessary:
• • Growth and development
  • Chest radiographs and, if pulmonary abnormalities are suggested, HRCT scans
  • Pulmonary function tests
  • Immunoglobulin trough level
    • Levels higher than or equal to 400 mg/dL are considered satisfactory.
    • Occasionally, levels higher than 500 mg/dL are required to clear certain viral infections such as enteroviral meningoencephalitis.
  • Liver function tests and, if abnormalities are identified, imaging studies of the liver and biliary tree
    • These studies are necessary to exclude malignancies or sclerosing cholangitis.
    • Sclerosing cholangitis is observed in persons with XHM.

Deterrence/Prevention

• Prophylactic antibiotics are recommended for patients who continue to experience frequent infections despite good immunoglobulin levels.

Complications

• X-linked agammaglobulinemia
  • In patients with XLA, attenuated live poliovirus vaccine may cause vaccine-associated poliomyelitis.
  • Chronic disseminated enteroviral infection may be associated with vasculitis, pneumonitis, and hepatitis.
  • Dermatomyositislike syndrome, a constellation of edema of subcutaneous tissue, skin rash, and muscle weakness, is unusual.
  • Chronic pulmonary disease (50% of patients) and chronic enteroviral meningoencephalitis remain the major complications of this disease. Very high doses of immunoglobulin (0.4 mg/kg q48h to 1g/kg/d for 3-12 mo) have been used by Quartier et al in the treatment of 3 patients with enteroviral meningoencephalitis. Trough levels as high as 3100-6300 mg/dL were achieved. Two patients survived, and clinical and cerebrospinal fluid abnormalities resolved. Hearing loss due to chronic otitis media or meningoencephalitis may affect up to a third of these patients.
  • Infectious complications cause death by age 20 years in approximately 15% of patients.
• Common variable immunodeficiency
• • Spruelike syndrome with malabsorption is observed in 10% of patients with CVID. Histologically, this resembles gluten-sensitive enteropathy (except for the absence of plasma cells). Infectious enteritis may imitate ulcerative colitis or Crohn disease, and both seem to occur more commonly in these patients.
  • Most patients with CVID and primary hypogammaglobulinemia develop pulmonary complications after several years of recurrent infections, sometimes despite appropriate IVIG therapy.
    • Although chest radiographs are useful, the criterion standard remains HRCT scans.
    • Using HRCT scans, 95% of patients studied by Kainulainen et al showed abnormalities. The most common findings were fibrosis (81%), bronchiectasis (73%), parenchymal scarring (45%), pleural thickening (36%), and, less commonly, emphysema or parenchymal nodules. Pulmonary function tests showed obstruction in 33% of patients. Follow-up using HRCT scans and pulmonary function tests revealed silent and asymptomatic deterioration despite appropriate IVIG therapy.
    • Cor pulmonale may ultimately result from chronic/recurrent lower respiratory tract infections.
  • Autoimmune diseases occur in 10-20% of patients. The most common disorders are Coombs-positive hemolytic anemia and idiopathic thrombocytopenic purpura. Neutropenia is observed less frequently. Pernicious anemia occurs in 10% of patients with CVID and is characterized by younger age of onset and an absence of antiparietal cell antibodies. Other less common autoimmune disorders have been reported, including thyroid diseases, Addison disease, diabetes mellitus, biliary cirrhosis, alopecia totalis, rheumatoid arthritis, systemic lupus erythematosus, polymyositis, sicca syndrome, and Guillain-Barré syndrome.
  • Granulomatous disease has been reported in 5.4-10% of patients with CVID.
    • Noncaseating granulomas can be localized in any organ, with the lungs, liver, and lymph nodes being the most frequent localizations, followed by the bone marrow and skin. Lung involvement led to restrictive lung disease and death in 4 of 17 patients studied by Mechanic et al. This entity should be differentiated from mycobacterial and fungal infections and from sarcoidosis.
    • The major distinguishing feature from idiopathic sarcoidosis is the level of immunoglobulins, which is increased in person with sarcoidosis and decreased in those with CVID. The Kveim test is not helpful because it returns a positive finding in up to 40-50% of CVID patients. ACE levels, a marker of macrophage activity, is elevated in approximately a third of these patients.
    • In vitro T-cell dysfunction in CVID patients with granulomatous disease may explain the higher risk of autoimmune diseases in these patients than in the rest of the group. In the small subset of patients with aggressive disease, corticosteroids are the treatment of choice.
  • The risk of cancer in CVID patients is 5-fold higher than in matched controls. A 47-fold increase in gastric cancer and a 30-fold increase in lymphoma have been reported; however, benign lymphoproliferative disorders are much more common, affecting up to 30% of patients and manifesting 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- and T-cell receptor rearrangement.
• IgA deficiency
• • Malabsorption, celiac disease, giardiasis, nodular lymphoid hyperplasia, pernicious anemia, primary biliary cirrhosis, and chronic hepatitis are observed.
  • The incidence of gastric and colon cancer is increased.
  • Patients have anaphylactic reactions to blood products containing IgA.
• Hypogammaglobulinemia: Encephalitis is a rare complication in hypogammaglobulinemic patients. It is frequently related to Enterovirus or coxsackievirus infection and, less commonly, to measles and papovavirus.
• Complications related to IVIG therapy
• • Complications include increased serum viscosity and more frequent thromboembolic events. The risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d) is also increased.
  • The most common adverse reactions are nonanaphylactic and are characterized by back and abdominal pain, nausea, vomiting, chills, fever, and myalgias. The infusion should be discontinued until the symptoms subside, and then it should be restarted at a slower rate.
  • True anaphylactic reactions are rare and occur seconds to hours after the infusion is started. Typical symptoms consist of flushing, facial swelling, dyspnea, and hypotension. The infusion should be stopped, and the patient should receive epinephrine, steroids, and antihistamines together.
  • The risk of renal tubular necrosis is increased in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease.
  • Hepatitis C virus (HCV) infection transmission is much less common now than in the past. Most of HCV RNA–positive patients contracted their infection in the 1980s, when serologic testing of blood donors was not available for this infection. Chronic liver disease in HCV RNA–positive patients is characterized by a severe clinical course, particularly in CVID patients. Hepatitis B and G viruses seem to play minor roles in the pathogenesis of chronic liver disease in these patients. A milder form of chronic liver disease with negative serology findings for HCV, hepatitis B virus (HBV), and hepatitis G virus (HGV) infections has been described in these patients. This form occurs an average of 36 months after the beginning of IVIG therapy and is thought to be related to immune phenomena or to an as yet undescribed viral infection. A small subset of patients without HCV, HBV, or HGV infection has a particularly severe course; in most, granulomatous disease of the liver has been identified.

Prognosis

• Before the immunoglobulin era, patients with XLA died at an early age because of the complications of infections with encapsulated bacteria. The advent of intramuscular immunoglobulin brought some clinical improvement, with only partial control of upper and lower respiratory tract infections, but patients still died before age 25 years. The introduction of IVIGs in the early 1980s resulted in significant improvement of infection control with prolonged survival.
• Most patients with XHM die in the first and second decades of life. The actuarial survival rate at 25 years is only 25%, and 80% of these patients develop liver disease by age 20 years.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to carefully screen patients before the administration of live attenuated vaccines
• Failure to perform prenatal screening for inherited disorders in patients with a family history of these disorders in order to discuss the indications of therapeutic discontinuation of pregnancy

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ballow M, O'Neil KM. Approach to the Patient With Recurrent Infections. In: Middleton E Jr, Reed CM, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WW, eds. Allergy: Principles & Practice. 5th ed. St. Louis, Mo: Mosby-Year Book; 1998:. 735-59.
• Behrman RE, Kliegman RM, Jenson HB, eds. Primary B-Cell diseases. In: Nelson's Textbook of Pediatrics. 16th ed. Philadelphia, Pa: WB Saunders; 2000:. 596-606.
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• Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. Jul 1997;131(1 Pt 1):47-54. [Medline].
• Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med. Oct 15 1997;127(8 Pt 1):613-7. [Medline].
• Quartier P, Debre M, De Blic J, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr. May 1999;134(5):589-96. [Medline].
• Sanna PP, Burton DR. Role of antibodies in controlling viral disease: lessons from experiments of nature and gene knockouts. J Virol. Nov 2000;74(21):9813-7. [Medline].
• Satterthwaite AB, Witte ON. The role of Bruton''s tyrosine kinase in B-cell development and function: a genetic perspective. Immunol Rev. Jun 2000;175:120-7. [Medline].
• Scholl PR, O''Gorman MR, Pachman LM, et al. Correction of neutropenia and hypogammaglobulinemia in X-linked hyper- IgM syndrome by allogeneic bone marrow transplantation. Bone Marrow Transplant. Dec 1998;22(12):1215-8. [Medline].
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Article Last Updated: Aug 25, 2006